Comparison of culture conditions and productivity of hydrocarbons between B. braunii strains at laboratory scale.
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\r\n\tThis book encompasses the new techniques, applications, challenges and opportunities in this fascinating area.
The FDA approvals of ipilimumab targeting the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), pembrolizumab targeting the programmed cell death protein 1 (PD-1), BRAF inhibitors vemurafenib and dabrafenib, and MEK inhibitor trametinib represent significant milestones in more effective treatment of advanced melanoma. However, it is clear that the use of these single-agent therapies have limitation clinically. For example, ipilimumab only showed 4.5% objective response rate when used alone in a Phase II clinical trial [1]. The efficacy of vemurafenib lasts only 6.7 months before the disease relapses especially in patients with metastatic melanoma [2]. Therefore, rational combination approaches are strongly preferred in order to improve the overall patient progression-free survival (PFS), overcome or delay the development of multi-drug resistance and reduce the incidents of side effects [3-6].
In this chapter, we will summarize the emerging combination therapy approaches from both clinical trial and preclinical research in the past five years.
BRAF is a serine/threonine growth signal transduction protein kinase from RAF family which plays important roles in the RAS/RAF/MEK/ERK pathway and directs cell division, proliferation and secretion [7]. BRAF inhibitors (BRAFi) are ATP-competitive ligands which inactivate the function of BRAF protein by either stabilizing the inactive form of kinase domain (sorafenib) or preferentially inhibit the active form of the kinase (vemurafenib, dabrafenib) [8, 9]. Various mutations of BRAF gene have been identified in cancers including melanoma, colorectal and ovarian cancer. Around 60% of human melanoma adopted the T1799A transversion in exon 15, which lead to BRAFV600E mutation and the over-activated monomer phosphorylation for BRAFV600E [9, 10]. The two FDA approved BRAFi (Vemurafenib and dabrafenib) selectively and potently block the activation of BRAFV600E and thus inhibit the MAPK signaling pathway. These drugs show very high clinical efficacy in metastatic melanoma patients harboring the BRAFV600E mutation [11-13]. Interestingly, in a clinical study which treated 43 patients with any V600 BRAF mutation including the rare V600R variant, five out of the six melanoma patients having V600R mutation had clinical response to the therapy of vemurafenib or dabrafenib (response rate 86%) [14].
The mechanisms of BRAF inhibitor vemurafenib (Vem) action, toxicity and the interaction between melanoma cells with T lymphocytes.
However, wide type BRAF melanoma tumors do not respond to vemurafenib or dabrafenib inhibition, although they are sensitive to the MEK inhibitors [9]. Paradoxically, in cells with RAS mutation and wild-type BRAF, treatment with vemurafenib or dabrafenib will promote the formation of BRAF-CRAF heterodimer and lead to the activation of subsequent MEK/ERK signaling and cell proliferation as shown in Figure 1 [5]. This mechanism is used to explain the observation of typical clinical side effects associated with the use of vemurafenib: nearly 25% of patients developed skin lesions and even cutaneous squamous cell carcinoma (CSCC). In addition, in vitro study has revealed that vemurafenib inhibits multiple off-target kinases including c-Jun N-terminal kinase (JNK), suppresses JNK-dependent apoptosis, and generates CSCC toxicity [15].
In general, due to alternative pathway activations and inter-and intra-patients melanoma genetic heterogeneity, various mechanisms of resistance to BRAF inhibition have been identified [10, 16-19]. As we mentioned before, melanoma tumors bearing wide type BRAF are intrinsically resistant to vemurafenib and dabrafenib. Tumor micro-environment also contributes to the innate resistance to BRAF inhibition in melanoma. For example, stromal cells secrete hepatocyte growth factor (HGF), which activates the HGF-receptor MET, MAPK and PI3K-AKT pathways [20].
Eventually, nearly all BRAF mutated melanoma tumors develop acquired drug resistance upon treatment with BRAF inhibitors. The disease progression arises as early as two-month continuous treatment [18, 19]. The mechanisms of acquired resistance to BRAF inhibition can be generalized into two categories: BRAFV600E-bypass mechanisms and MAPK-bypass mechanisms.
First, the BRAFV600E-bypass mechanisms reactivate MAPK signaling and lead to ERK-dependent tumor cell survival and proliferation (Figure 2A). COT, which is coded by gene MAP3K8, is a MEK kinase. The overexpression of COT or amplification of MAP3K8 directly activates MEK signaling without the participation of RAF protein [21]. The mutant of MEK1C121S increases catalytic capability and circumvents BRAF to activate basal level of ERK phosphorylation [22]. Before the treatment of vemurafenib or dabrafenib, melanoma cells with BRAFV600E mutation have over-activated monomer BRAF/MEK/ERK cascade which forms an ERK-dependent negative feedback loop. This negative feedback loop reduces the expression of the active RAS-GTP. In the presence of vemurafenib or dabrafenib, ERK phosphorylation level is rapidly reduced and the feed-back suppression on RAS activation is abolished (Figure 1). Therefore, eventually the ERK cascade level is restored through RAS over-activation. NRAS mutants including NRASQ61K and NRASQ61R can drive ERK activation through ARAF or CRAF homo-or hetero-dimers which are alternative MEK activators [23]. The combinations of BRAF inhibition plus MEK or ERK inhibition have showed efficacy of overcoming the resistance through these BRAF V600E-bypass mechanisms [24-26], leading to the recent FDA approval of dabrafenib plus trametinib combination therapy for advanced melanoma.
Second, the MAPK-bypass mechanisms allow melanoma cells to escape from the cytotoxicity of BRAF or MEK inhibition through the activation of ERK-independent survival pathways (Figure 2B). The PI3K-AKT signaling pathway can be activated through the overexpression of receptor tyrosine kinases (RTKs), for example, insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) and platelet-derived growth factor receptor beta (PDGFRβ) [27]. The elevated levels of IGF-1R, PDGFRβ or HGF can also stimulate another receptor tyrosine kinase, MET, and increase the activity of PI3K. Phosphatase tensin (PTEN) is a negative regulator of PI3K. The PTEN loss-of-function mutation induces the resistance of BRAF inhibition and reduces the PFS of dabrafenib therapy in melanoma patients due to the PI3K activation [28]. Moreover, the upregulation of cyclin D1 can activate cyclin-dependent kinase 4 (CDK4) and 6 (CDK6) and make melanoma cells less dependent on MAPK signaling in cell cycle progressing [29].
The mechanisms of acquired resistance to BRAF inhibition.
Additionally, Jaehyuk Choi et al has reported a BRAFL505H mutation which changes an amino acid residue in BRAF-vemurafenib interface and causes the resistance to vemurafenib treatment in vitro [30]. Since vemurafenib is a substrate of the ATP-binding cassette sub-family G member 2 (ABCG2), the overexpression of ABCG2 in BRAFV600E melanoma cell lines has caused the increasing of vemurafenib efflux in vitro [31]. The elucidation on the mechanism of acquired-resistance to BRAFi opens a door to rationally design and explore the proper combination strategies to overcome or delay the development of BRAFi resistance.
Trametinib, which is approved by FDA in May 2013 as a monotherapy agent against advanced melanoma with BRAFV600E and BRAFV600K mutations, is a first-in-class, orally available, allosteric (non-ATP-competitive) MEK1/MEK2 inhibitor (MEKi) [32, 33]. It selectively inhibits MEK, the down-stream kinase protein of RAF in the RAS-RAF-MEK-ERK pathway. As a result, melanoma cells with acquired resistance to BRAFi are commonly cross-resistant to MEKi such as trametinib or selumetinib, another selective allosteric MEKi [24, 34]. This mechanism explains the clinical trial results in which trametinib monotherapy fails to significantly benefit patients who have already developed acquired BRAFi resistance [35]. In contrast to the use of a BRAFi, no CSCC side effects are observed among the patients received trametinib treatment in clinical trials [13, 32]. However, similar to the use of vemurafenib, disease progression occurs within 6-7 months in patients receiving single-agent trametinib treatment [36]. Nevertheless, a retrospective analysis of 23 patients, who were first treated with MEKi and upon progression with a selective BRAFi, shows that the median time to progression (TTP) has been prolonged to 8.9 months from 4.8 months using a single-agent MEKi or 4.4 months for a single-agent BRAFi treatment, respectively [37]. However, a recent clinical trial indicated that if melanoma patients were treated with a BRAFi first then MEKi therapy, no confirmed response was observed [35]. This indicates that optimal treatment schedule and sequence is important for the melanoma therapy targeting the MAPK pathway.
Given that the mechanisms of tumor cells develop resistance to BRAFi partially by reactivating the ERK cascade and side effects such as CSCC are RAF-dependent, combining BRAFi with MEKi has attracted lots of research interest in order to further block the MAPK signaling pathway. In vitro and murine models first show the synergistic anti-proliferation and anti-tumor growth effects using the combined BRAFi and MEKi treatment [9, 27, 38, 39]. Further, this combination overcomes the acquired resistance to BRAFi [27, 38] in both cellular based assay and mouse xenograft models. In addition, the combined inhibition of BRAF-MEK suppresses the paradoxical BRAFi-induced MAPK signal elevation in melanoma cells and reduces the incidences of skin lesions in a rat model [9].
When it comes to the clinical trial data, the combined inhibition of BRAF-MEK has presented significant improvements of major patient benefits (PFS and overall survival). A phase I/II trial (ClinicalTrials.gov, NCT1072175) investigated the combination of oral dabrafenib (150 mg twice per day) plus oral trametinib (1 or 2 mg daily) (combination 150/1 and 150/2) versus monotherapy of dabrafenib (150 mg twice per day) over 108 metastatic melanoma patients bearing either V600E (92 patients) or V600K (16 patients) BRAF mutation [12, 36]. Median PFS in combination 150/2 group reached 9.4 months, compared to 5.8 months in the dabrafenib monotherapy group (hazard ratio 0.39, 95% confidence interval 0.25 to 0.62). The incidence of CSCC adverse events among combination 150/2 group is non-significantly lower than that among monotherapy group (7% versus 19%, P=0.09). But more frequent cases of pyrexia which is not common in trametinib single treatment have been reported in combination 150/2 group (71%, with recurrent rate 79%), as compared with dabrafenib monotherapy group (26%) [40]. These promising data lead to an accelerated FDA approval of the combination of dabrafenib (BRAFi) and trametinib (MEKi) for the treatment of unresectable or metastatic melanoma patients with BRAF V600E or V600K mutation, although further phase III studies with recruitment of more patients comparing the combination therapy with dabrafenib or vemurafenib single treatment (ClinicalTrials.gov, NCT01584648, NCT01597908) are still being assessed.
In addition, several ongoing phase I/II clinical trials now have shown that generally the combination of other BRAFi and MEKi is well tolerated in patients with or without receiving BRAFi treatment before (ClinicalTrials.gov, NCT01271803 vemurafenib (BRAFi)+cobimetinib (MEKi), NCT01543698 LGX818 (BRAFi)+MEK162 (MEKi)) [41-43] and overall response rate has increased comparing to the monotherapy groups, although the anti-tumor efficacy data haven’t been released.
The activation of PI3K/AKT/mTOR pathway have been widely proved to be one of the major mechanisms of intrinsic or acquired resistance to both DNA-methylation agents (e.g. dacarbazine) and targeted BRAF inhibitor therapy (Figure 2). Some cell lines that are cross-resistant to both BRAFi and MEKi, are still sensitive to the inhibition of AKT/mTOR [34]. On the other hand, mechanistic study revealed evidences of a negative crosstalk between RAF/MEK/ERK and PI3K/AKT/mTOR pathways through RAS kinase. Therefore, when the downstream mTOR function is blocked, PI3K will be able to activate MAPK pathway via a switch of RAS [44, 45]. These investigations suggest a promising combination strategy of targeting MAPK pathway together with PI3K/AKT/mTOR cascade. Several preclinical studies widely proved that in MAPK inhibition sensitive melanoma cell lines, co-targeting PI3K/AKT/mTOR effectively induces cancer cell apoptosis with down-regulated anti-apoptotic BCL-2 family proteins [34, 46-48]. Such a co-targeting strategy can also postpone the emergence of acquired resistance to BRAFi dabrafenib mediated by PTEN mutation or disruption [49, 50]. Further, the dual inhibition of two pathways has successfully overcome NRAS mutation mediated resistance to MAPK blockade in vitro and induced xenograft tumor regression in vivo [34, 38, 51]. Finally, the combination of vemurafenib (BRAFi) or selumetinib (MEKi) with BEZ235 (dual PI3K and mTOR1/2 inhibitor) has been shown to overcome the PDGFRβ-driven resistance to MAPK pathway inhibition [52].
A series of Phase I studies have evaluated the clinical relevance of the combination therapy which co-targets PI3K/AKT/mTOR and RAF/MEK/ERK pathways in terms of the incidence on severe side effect and anti-tumor efficacy in 236 patients. These patients have advanced cancers including melanoma, colorectal, pancreatic and non-small cell lung cancers. Results from three combination groups (AKTi MK2206+MEKi selumetinib, NCT01021748; AKTi GSK2141795+MEKi trametinib, NCT01138085; mTOR inhibitor everolimus+MEKi trametinib, NCT 00955773) are compared to the single treatment groups [53]. Overall, the combination therapy did not provide significant increase of tumor control rate (64.6% for combination, 52.7% for monotherapy, P=0.16), although all five colorectal patients with co-activation of both pathways in combination group achieved tumor regression to varied extent between 2% and 64%. However, this combination strategy causes significant higher rates of drug-related grade III and above side effects (53.9% for combination, 18.1% for monotherapy, P < 0.001). Furthermore, two clinical trials which involve the combination therapy of BRAFi or MEKi with AKTi DNE3 recently have been terminated due to the safety concerns of the toxic properties of DNE3 (ClinicalTrials.gov, NCT02087254 and NCT02095652). Nevertheless, in another ongoing phase I/II trial which measures the safety and efficacy of a well-tolerated pan-PI3K inhibitor BKM120 combined with vemurafenib therapy, preliminary data reveals that a vemurafenib-refractory melanoma patient with PTEN expression achieved a 35.9% reduction in target tumor (ClinicalTrials.gov, NCT01512251) [54]. In general, drug-related toxicity is one of the major issues for this cross-pathway targeted combination therapy and patients genetic profiling is very important to achieve the maximum objective response.
Melanoma is a vascular tumor. The abnormal expression of the epidermal growth factor (EGF) family protein and the up-regulation of EGFR-mediated alternative survival pathway have critically shaped the response of melanoma to the current chemotherapy agents [55-58]. In a recent study by Sun et al, six out of sixteen melanoma cell lines display acquired EGFR expression after the development of resistance to BRAFi and MEKi [59]. Even before the FDA approval of BRAFi and MEKi, the combination of bevacizumab, a recombinant human monoclonal antibody VEGF inhibitor, with a specific chemotherapy agent (for example, fluorouracil [60] or fotemustine[61]), has become a first-line treatment for metastatic melanoma patients. Clinical trials that study the combination of anti-angiogenic agents with cytotoxic agents have achieved promising anti-tumor activity, although tolerability issues exist [62]. VEGF blockage has been shown to enhance the efficacy of a GM-CSF-secreting immunotherapy in vitro [63]. In addition, a VEGF receptor-2 inhibitor, semaxanib, prolonged both the complete and partial response time of an immunomodulatory drug, thalidomide, over 10 recurrent metastasis melanoma patients without showing significant drug-drug interaction toxicity in a phase II trial [64].
Along with the rapid development of targeted melanoma therapeutics, the combined inhibition of VEGFR plus PDGFR or mTOR has shown synergy anti-tumor effects on mouse models of B16 metastatic melanoma without increasing toxicity [65, 66]. A large-scale, unbiased drug screening study, which aims to discover effective genotype selective combinatorial therapeutics of vemurafenib-resistant BRAF and RAS mutant melanoma, identifies a triple BRAF+EGFR+AKT inhibition as highly effective approach [3]. In the year of 2010, combination of bevacizumab with an mTOR inhibitor, everolimus, was evaluated in a phase II trial for patients with metastatic melanoma [67]. The treatment was well tolerated in most patients. Seven out of fifty-seven patients (12%) receiving combination therapy have shown major responses, although the median PFS was only 4 months. This year (2014), in a phase II trial that combines bevacizumab and sorafenib, which is an inhibitor of both RAF kinase and VEGFR-2/PDGFRβ signaling, no objective tumor responses are seen in all the fourteen patients receiving treatment [68, 69]. Interestingly, the median TTP of patients with low VEGF (<300 pg/ml) was longer than that of patients with high VEGF (50 weeks versus 15 weeks, P=0.02). Therefore, the levels of VEGF in patients do influence the tumor progression profile (ClinicalTrials.gov, NCT00387751).
Since the abnormally activated (phosphorylation) of ERK and AKT constitutively exist in melanoma cells and promote the disease progression especially metastasis, blocking ERK or AKT pathway can sensitize the metastatic melanoma to the apoptosis induced by chemotherapeutic agents including cisplatin, temozolomide, DTIC and arsenite [70-72]. With the understanding of tumor biology about the programmed cell apoptosis and the rapid development of agents that can trigger the cell death process in melanoma, the combination of a MAPK inhibitor with a BCL-2 inhibitor (ABT-737 [73] or navitoclax [74]), or a MDM2 antagonist nutlin-3 [75], has synergistically induced apoptosis of melanoma in vitro and suppressed xenograft tumor growth in vivo. A comparative analysis on the samples collected from patients receiving vemurafenib or dabrafenib/trametinib combination treatment showed that BCL-2 expression level is closely related to the onset of MAPK inhibition resistance [74]. Clinical trials are being conducted to investigate the combination of BCL-2 inhibitor (BH3 mimetics) navitoclax and vemurafenib [74].
Due to the heterogenetic characteristics of melanoma disease, Vultur A et al [76] recently report that MEK or BRAF inhibition can potentially strengthen the invasion property of human melanoma cells by about 20%. As a result, co-inhibiting kinases that are actively involved in cell invasion process, such as RTK, STAT3 and Src, together with MEK inhibition has effectively abolished the invasive phenotype and further caused the tumor cell death in a 3D matrix model.
Metformin, a biguanide oral anti-diabetic drug, has been discovered with antitumor activity in various cancer types including melanoma. Although the exact mechanisms remain to be elucidated, accumulating data suggest that metformin can activate AMP-activated protein kinase (AMPK) and thus increase the activities of VEGF and ERK in BRAFV600E mutated melanoma cells [77]. AMPK negatively regulates malignant cell proliferation and viability [78]. The combination of vemurafenib and metformin has shown synergistic anti-proliferative effects on six out of eleven tested BRAFV600E melanoma cell lines [79]. Pilot clinical studies that evaluate the safety and efficacy of metformin combination therapies (plus dabrafenib or trametinib) are now recruiting patients (ClinicalTrials.gov, NCT0184000, NCT02143050).
Unlike the cutaneous melanoma, over-activation of MAPK pathway in uveal melanoma is associated GNAQ or GNA11 mutations instead of BRAF or RAS mutations [80]. Protein kinase C (PKC) inhibitors such as enzastaurin or AEB071 induce apoptosis in GNAQ-mutant but not in GNAQ wild type uveal melanoma cells [81]. The level of ERK phosphorylation also decreases in these cells when they are treated using PKC inhibitors [81]. Chen et al. has recently confirmed the synergy of the combination using a PKC inhibitor with a MEKi (PD0325901 or MEK162) in GNAQ/11 mutant uveal melanoma cells [82].
Understanding the mechanisms of resistance to MAPK inhibition in melanoma can lead to rational combination designs in order to overcome acquired drug resistance to BRAF inhibitors. For example, our lab recently identified a synergistic combination in which a novel tubulin inhibitor ABI-274 combined with vemurafenib could overcome the acquired vemurafenib-resistance [83]. This combination treatment effectively arrested the vemurafenib-resistant melanoma cells in both G0/G1 and G2/M phases and induced strong apoptosis through the down-regulation of AKT phosphorylation. In addition, the combination of a MEKi (TAK-733) with an Hsp90 inhibitor (ganetespib) induces tumor regressions in vemurafenib-resistant xenograft models also through the depletion of AKT signaling [84]. With the finding that up-regulated cyclin D1 expression is critical for the survival of vemurafenib-resistant cells, a selective inhibitor of cyclin dependent kinase (CDK) 4/6, LY2835219, has been reported to overcome the reactivation of MAPK signaling in vemurafenib-resistant BRAFV600E melanoma [85].
Given the unsatisfactory results of cytokine-based melanoma immunotherapy (recombinant interferon-α 2b and high dose interleukin-2) in the past decade, the development and approval of ipilimumab (anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody) in 2013 have marked a breakthrough of immune-checkpoints blockade therapy [86]. CTLA-4 (CD152) expresses on the surface of active T-lymphocytes and inhibits the initial T-cell proliferation and migration to the tumor tissue [87]. CTLA-4 antibodies preferentially target the suppressive regulatory T cells and prevent them from being hijacked by tumors [88]. In a double-blinded phase III study in 676 patients with pretreated and refractory metastatic melanoma, ipilimumab at the dose of 3 mg/kg achieved a median OS of 10 months [86]. In a meta-Kaplan-Meier-analysis of data collected from 1,861 melanoma patients in a clinical trial, a plateau of survival curve starts from around 3 years after ipilimumab treatment with follow-up extends as long as ten years, indicating a long-term survival benefits of ipilimumab therapy (ClinicalTrials.gov, NCT01844505). In addition, ipilimumab showed good tolerance and efficacy in several other clinical trials in which it was combined with a standard chemotherapy agent such as dacarbazine, fotemustine or temozolomide [89].
Another success of immune-check point blockade strategy is the development of anti-programmed death-1 (PD-1) antibodies, represented by pembrolizumab (MK-3475) and nivolumab [90, 91]. Pembrolizumab, as the first-in-class PD-1 inhibitor, has obtained FDA approval in September 2014 for patients with advanced or unresectable melanoma. The cDNA of PD-1 (CD279) is first cloned in programmed death T cells although PD-1 itself does not directly induce apoptosis. PD-1 is over-expressed on the surface of dysfunctional activated T-cells and contributes to the maintenance of T cell dysfunction (exhaust) phenotype and proliferation disability in the tumor site [92]. Two counter receptors of PD-1 have been identified: PD-L1 and PD-L2. PD-L1 is more frequently and exclusively expressed in various tumor cells; therefore, antibodies targeting PD-L1 (MPDL3280A and BMS-936559) also have anti-tumor activity in advanced cancer including melanoma [91, 93]. The PD-1-PD-L1 ligation retards the recognition and destroying of tumor cells by CD8+cytotoxic T-lymphocytes [87]. As a result, blocking PD-1 or PD-L1 will reverse the cancer cell immune escape. Because both CTLA-4 and PD-1 are key negative receptors that cooperatively modulate the adaptive immune response in tumor progression, their combination has been shown to be synergistic in B16 melanoma tumors without overt toxicity [94].
In a cohort phase I trial that studied the concurrent administration of ipilimumab and nivolumab to 53 patients with advanced, treatment-resistant melanoma, more than 80% tumor reduction was observed in 30% patients after 12 weeks treatment at the maximum tolerated dose. Twenty-one out of fifty-three patients had objective responses and over 80% of these patients had tumor regression. Grade 3/4 adverse events are diagnosed in 53% patients but the toxicities are manageable with immune-suppressants [95]. Consequential trials with more enrollment number of patients are necessary to further evaluate the safety and efficacy of this promising double immune-checkpoints blockage therapy comparing with each of its monotherapy regiments.
Finally, combinatorial clinical trials using ipilimumab with other immunotherapy agents have shown some favorable therapeutic benefits. For example, combination of ipilimumab with peginterferon α-2b (pegylated interferon α-2b) in patients with unresectable melanoma both demonstrated significant increase of response rate and OS comparing with the monotherapy arm [96, 97] in recent phase I trials.
Checkpoint blockade immunotherapy and MAPK targeted chemotherapy have distinct clinical profiles. For example, targeted therapy has relative higher initial response rate (~60% for BRAFi) with rapid onset of effect, but its efficacy restrictively rely on the continuous treatment and the therapeutic response is usually not durable due to the quick development of acquired drug resistance. In contrast, immunotherapy has much a lower response rate (4.5% for ipilimumab), delayed onset of effect and difficulty in predicting patient outcome, but it has shown potentially durable responses and long-term survival benefit even off treatment. In addition, since the MAPK pathway is not required in the process of anti-tumor immune response, blocking MAPK signaling should not interfere with the efficacy of checkpoint blockade immunotherapy. Therefore, it seems very rational that the combination of a MAPKi and an immunotherapy agent such as ipilimumab or pembrolizumab can maximize the therapeutic benefits in advance melanoma.
Interestingly, BRAF and MEK inhibition displayed an “endogenous vaccine-like” effects in melanoma cells [98]. Cytotoxic agents like BRAFi induce tumor cell death and promote the uptake and presentation of tumor antigens to the effector immune cells (T cells and B cells) through antigen-presenting cells [54]. MEK inhibition, BRAFV600E RNA silencing or BRAF inhibition by PLX4720 increases the CD4+ and CD8+ lymphocytes mediated T-cell infiltration and reduce the level of immune-suppressants including IL-6, IL-10 or VEGF [99-101] in mice. The expression of PD-L1 is found to be elevated in BRAFi-resistant melanoma cells and it is mediated through the off-target activity of BRAFi in JUN and STAT3 signaling [102]. However, Vella et al has published a paper in 2014 and stated that they have not found any impact of dabrafenib treatment on T lymphocytes. trametinib alone or in combination with dabrafenib has suppressed T lymphocyte proliferation, cytokine secretion and antigen-specific expansion in their isolated T lymphocyte and monocyte-derived dendritic cells. These findings should be carefully tested in vivo to evaluate the clinical relevance [103].
As for the clinical practice, dose-limiting hepatotoxicity issues have led to the premature termination of the first phase I study on combination of ipilimumab with vemurafenib (ClinicalTrials.gov, NCT01400451). This signified the complexity of adverse effect in combined therapy of immune-regulating agents and kinase inhibitors. Another phase I study of ipilimumab plus dabrafenib, or ipilimumab plus the combination of dabrafenib with trametinib is still active and a phase II study is exploring the safety and efficacy of sequential administration of vemurafenib followed by ipilimumab (ClinicalTrials.gov, NCT01767454, NCT01673854). The data of these most recent trials will be released in the near future.
Extensive efforts and remarkable progresses have been made to discover and investigate rational approaches in combination melanoma therapy since the recent approval of MAPKi and immune checkpoints blockade antibodies. A number of new targeted or immune drugs for metastatic melanoma are currently under commercial development or late stage clinical trials, some of which will likely be approved in the next few years. Quality of life for many melanoma patients has been dramatically increased. However, significant challenges still remain. While some clinical evidence has really raised the expectation of survivals for patients with advanced melanoma, the benefits of combination therapy are usually accompanied by limitations. Comprehensive genetic profile and tailored patient matching is essential for targeted therapy, while biomarkers are critical to predict the patient immunotherapy response. Drug-related toxicity for combination treatment usually is not a simple one-plus-one situation, and potential drug-drug interactions, especially the combination of a targeted agent with an immunotherapeutic agent must be carefully evaluated in order to achieve both fast and durable responses. Adverse effects should be closely monitored and potential alternative dosing regiments is worth further exploration. Optimized dose schedule may help to delay the resistance development and reduce the frequency of adverse effect. For example, intermittent doses of BRAFi was able to enhance the tolerance in combination with immunotherapy, decrease the paradoxical MAPK activation, which might be the main cause of severe toxicity in clinical trial [104]. Solid evidence of synergistic combination in preclinical research must be established before clinical trial conduction. In fact, with the relatively large number of available targeted agents and immunotherapeutic agents for metastatic melanoma, the huge number of possible drug combinations coupled with dosing sequences or schedules already presents a significant challenge in designing proper clinical trials. To test all the possible drug combinations along with different dosing sequences clinically will not only have low benefits to patients, but is also a huge financial burden to the society. Carefully designed, predictive preclinical studies will be essential to provide critical supports for rational prioritization of clinical trials using drug combinations. Finally, clear understandings of various combination mechanisms and patient genetic profiles are critically important for the development of new combination approaches, prediction of expected therapy response and potential side effects. With the rapid advances in this field, it is likely that optimal combination treatments will great improve the management of advanced melanoma in cancer patients.
AMPK: 5\' adenosine monophosphate-activated protein kinase
BRAF: B-Raf protein
BRAFi: BRAF inhibitor
CDK: Cyclin dependent kinase
CR: Complete response
CTLA-4: Cytotoxic T lymphocyte-associated antigen 4
ERK: Extracellular signal-regulated kinase
HR: Hazard ratio
JNK: c-Jun N-terminal kinase
MAPK: Mitogen-activated protein kinase
MEKi: MEK inhibitor
MHC: Membrane histocompatibility complex
mTOR: Mammalian target of rapamycin
ORR: Overall response rate
OS: Overall survival
PD-1: Programmed cell death 1
PD-L1: Programmed cell death 1 ligand 1
PDGFR: Platete-derived growth factor receptor
PFS: Progression-free survival
PI3K: Phosphoinositide 3-kinase
PKC: Protein kinase C
PR: Partial response
RTKs: Receptor tyrosine kinases
TCR: T cell receptor
VEGF: Vascular endothelial growth factor
VEGFR: Vascular endothelial growth factor receptor
This work was supported by NIH grants R01CA148706. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Jin Wang acknowledges the support of the Alma and Hal Reagan Fellowship.
Botryococcus braunii is a colonial microalga Trebouxiophyceae, distributed in brackish and sweet water [1]. It reaches densities of 1.4 × 106 colonies/L [2], and its geochemistry significance is important. Paleobotanical studies suggest that it is one of the largest sources of hydrocarbons in oil-rich deposits dating back to the Ordovician period [1, 3, 4, 5]. It is the only colonial microalga that accumulates and secrets liquid hydrocarbons (Figure 1), and depending on the strain and growing conditions, race B can accumulate hydrocarbons up to 85% and race A up to 61% of their dry weight.
\nB. braunii race B colony secreting liquid hydrocarbons.
B. braunii is related with Characium vaculatum and Dunaliella parva [1]. Due to the hydrocarbons and the molecular phylogeny of B. braunii [6], it is classified in three races (A, B, and L). Race A produces n-alkadienes and alkatrienes of C23–C33 [7], although two unusual hydrocarbons have been characterized, the triene C27H51 and tetraene C27H48 [1]. Race A hydrocarbon dry weight varies from 0.4 to 61% [7, 8]. Race B produces triterpenoids hydrocarbons known as botryococcenes (CnH2n−10, n = 30-37) [9] and methylsqualenes C31–C34 [10, 11]. The botryococcenes can be from 27 to 86% of the dry weight [12]. Race L produces a tetraterpene C40 known as lycopadiene and constitutes from 0.1 to 8% of the dry weight [13, 14]. This race contains 5% of lycopatriene, lycopatetraene, lycopapentaene, and lycopahexaene [15]. In addition, a race S is proposed, which synthesizes saturated n-alkanes C18 and C20, and epoxy-alkanes; however, its existence is not yet fully accepted [6].
\nAfter the hydrocracking process and subsequent distillation, race B hydrocarbons become biofuels currently used in internal combustion engines [16] as shown in Figure 2.
\nHydrocarbons produced by the B. braunii races. Biofuels derived from race B are shown. RON, research octane number = 92–98, this is a measure of autoignition resistance in a spark-ignition engine. In the USA: regular (97 RON) and premium (95 RON). Adapted from [16, 17, 18].
B. braunii races differ also by its morphological and physiological characteristics. Cells from A and B races are of 13 μm × 7–9 μm, and those of L race are 8–9 μm × 5 μm [19].
\nEach colony is constituted by a group of 50–100 piriform cells embedded in a hydrocarbon network and the extracellular matrix (ECM). This ECM contains three main components: (1) a fibrous cell wall surrounding each cell and having β-1,4-and/or β-1,3-glucans including cellulose; (2) the intracolonial space constituted by a network of liquid hydrocarbons; and (3) a fibrillary sheath composed mainly of arabinose and galactose polysaccharides, holding the liquid hydrocarbons [20].
\nB. braunii may have a hetero-, mixo-, or phototrophic grow and the morphology will depend on the C source and the amount of light [21]. The hydrocarbon production is associated with the cell division [22], likely due to the localization of the enzymes involved in the alkadienes, alkatrienes (race A), and botryococcenes (race B) biosynthesis [23].
\nOther difference among the races is the keto-carotenoid accumulation in the stationary phase of cultures. Races B and L change color from green-brown to orange, and race A changes from green to yellow-orange [1]. The production of carotenoids is also a stress response by environmental factors. The DAD1 gene expression, a suppressor of programmed cell death, was reported in race B, under stress conditions at 10–60 min [24]. B. braunii is tolerant to desiccation and extreme temperatures, which allows its global dispersion in different environments [25]. The reproduction mechanism of B. braunii seems to be autosporic [26].
\nSymbiotic bacteria have been reported after microscopic observations, and an ectosymbiont α-proteobacteria (BOTRYCO-2) that promotes the productivity of biomass and hydrocarbons was described [2, 27].
\nCharacteristic alkadienes and alkatrienes of race A have double links and similar stereochemistry as oleic acid. Experiments with labeled fatty acids have shown that this one is the main precursor by the long-chain fatty acids (LCFAs) pathway, followed by a decarboxylation process [1, 17, 28, 29]. The first step is the elongation of oleic acid (18:1 cis-Δ9) and its isomer elaidic acid (18:1 trans-Δ9). The acyl-CoA reductase and decarbonylase enzymes in race A microsomes suggest an alternative mechanism where the LCFAs are reduced to aldehydes and decarbonylated to produce alkadienes and alkatrienes [17, 30]. Race A transcriptome allowed the identification of six candidate genes potentially involved in this biosynthesis [31].
\nThe analysis of race B transcriptome and other evidences suggests that the biosynthesis of isoprenoids comes from the deoxyxylulose phosphate/methylerythritol phosphate (DXP/MEP) pathway [32, 33, 34]. Expressed sequence tag (EST) markers for enzymes of the DXP/MEP pathway [34], as well as multiple isoforms of enzymes for the 3-phospho-
The first step is the formation of 1-deoxy-
Biosynthesis of tri- and tetraterpenes in B. braunii race B. (a) FPP production; (b) carotenoid production from GGPP; (c) squalene production from FPP; (d) methylated botryococcene production; (e) methylated squalene production. BSS, Botryococcus squalene synthase; CtrB, phytoene-synthase; DXR, 1-deoxy-d-xylulose-5-phosphate reductase; DXS, 1-deoxy-d-xylulose-5-phosphate synthase; FPPS, farnesyl diphosphate synthase; GPPS, geranyl diphosphate synthase; NADPH+ and NADP+, nicotinamide adenine dinucleotide phosphate (reduced and oxidized); PPi, inorganic pyrophosphate; PSPP, cyclopropyl presqualene diphosphate; SAM, S-adenosyl methionine; SAH, S-adenosyl-l-homocysteine; SSL, squalene synthase-like; SMT, squalene methyltransferase; TMT, triterpene methyltransferase. Adapted from [17, 34].
The characterization of three DXS isoenzymes in race B shows that they are active and have similar kinetic parameters, which increases the metabolic flow for the production of terpenoids [35]. The DOXP is reduced by the DXP reductoisomerase (DXR) to 2-C-methylerythritol-4-phosphate (MEP), and converted to isopentenyl diphosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). In the B. braunii transcriptome, only one DXR has been found [34]. The next step involves condensation of IPP and DMAPP to form geranyl diphosphate (GPP), and the addition of other IPP produces farnesyl diphosphate (FPP) [17] (Figure 3a). Two B. braunii genes code for farnesyl diphosphate synthase isoenzymes (FPPS) with an amino acid identity of 72% [34].
\nAddition of another IPP forms the geranylgeranyl diphosphate (GGPP), precursor of the tetraterpenoid carotenoids (Figure 3b). This begins with the formation of a trans-isoprenyl diphosphate by the phytoene synthase (CtrB) enzyme, condensing two GGPP molecules in two steps with the release of pyrophosphate. In the first step, (1R, 2R, 3R)-prephytoene diphosphate is produced from half cyclopropyl (C1′-2-3) reordered to provide 15-cis-phytoene, which can be converted into a wide variety of carotenoids [34, 36, 37, 38]. All are important antioxidant photoprotectors and modulators of the function of membrane proteins for photosynthetic complexes [39].
\nThe squalene production [40] starts with the Botryococcus squalene synthase (BSS) enzyme, using two FPP molecules. Botryococcenes production uses also two FPP molecules but the product is the intermediary cyclopropyl presqualene diphosphate (PSPP) (Figure 3c). With NADPH, the PSPP has two options; one forms the botryococcene with a C3-C1 connection between the FPP molecules (Figure 3d). The other option forms a C1-C1′ between two FPP molecules producing squalene that will be methylated (Figure 3e) further on. These reactions are catalyzed by squalene synthase-like (SSL) enzymes. Three SSL genes have been identified but none is directly related with the botryococcene biosynthesis [41]. However, when the 3 SSLs enzymes were mixed in vivo and in vitro, botryococcene (SSL-1 + SSL-3) or squalene (SSL1 + SSL-2) was synthesized. SSL-1 condenses two FPP molecules to produce PSPP [42], demonstrating the versatility and potential for metabolic engineering of botryococcene biosynthesis.
\nMost botryococcenes are excreted to the ECM where they are methylated. The di- and tetramethyl forms are related to six genes coding for triterpene and squalene methyltransferases (TMT, SMT) [43] (Figures 3d and 3e). The botryococcenes are methylated to produce C31–C37 hydrocarbons, C34 being the main in race B. Three cyclic botryococcene C33 molecules and a trimethylsqualene isomer were recently found [44]. Also, two squalene epoxidase (BbSQE-I and -II) enzymes converting squalene into membrane sterols were identified [45]. Data of the B. braunii race B nuclear genome will allow the search for possible regulatory routes of this singular metabolism [46].
\nThe formation of lycopadiene of race L is similar to the squalene. In the B. braunii transcriptome, there are two homologous contigs to squalene synthase (SS) [31]. One encodes a squalene synthase (LSS) and the other for a lycopaoctaene synthase (LOS). LOS uses preferentially in vivo GGPP, and C15 and C20 prenyl diphosphates as substrates [15] (Figure 4).
\nLycopadiene biosynthetic pathway. (a) Reduction of GGPP to PPP and condensation by LOS. (b) LOS condensation of GGPP to form phytyl diphosphate and reduction to lycopaoctaene. (c) FPP use by LSS or LOS for squalene production. DXR, 1-deoxy-d-xylulose-5-phosphate reductase; DXS, 1-deoxy-d-xylulose-5-phosphate synthase; FPP, farnesyl diphosphate; FPPS, farnesyl diphosphate synthase; GGPP, geranylgeranyl diphosphate; GPPS, geranyl diphosphate synthase; GPPR, geranyl diphosphate reductase; NADPH+ and NADP+, nicotinamide adenine dinucleotide phosphate (reduced and oxidized); PPi, inorganic pyrophosphate; PPP, phytyl diphosphate; PLPP, prelycopaoctaene diphosphate; LOS, lycopaoctaene synthase; LSS, B. braunii race L squalene synthase. Adapted from [15].
There are two biosynthetic mechanisms for lycopadiene from C20 prenyl diphosphate intermediates. In one, the GGPP reduction by a GGPP-reductase produces phytyl diphosphate (PPP), and LOS condenses two PPP molecules producing lycopadiene (Figure 4a). In the other one, LOS condenses two GGPP molecules producing prelycopaoctaene diphosphate (PLPP), which rearranges into lycopaoctaene. Finally, lycopadiene seems to be produced by enzymatic reductions not yet identified (Figure 4b).
\nLOS may also form squalene from FPP (Figure 4c). These results show the plasticity of L race to synthesize squalene and lycopadiene.
\nECM contains long chains of polymerized polyacetal hydrocarbons joined to specific hydrocarbons of each race. There is a fibrillary sheath that envelops the entire colony, formed mainly by arabinose (42%) and galactose (39%). The cell wall contains β-1,4 and/or β-1,3 glucans making a cellulose-like polymer [20].
\nAlso, there\'s a biopolymer resistant to nonoxidative chemical degradation as acetolysis. This biopolymer resembles sporopollenins [1] of the outer walls of pollen grains and spores of microorganisms [47]. It seems to be formed by oxidized carotenoid polymers and phenolic compounds that absorb UV-B light as p-coumaric and p-ferulic acids [48].
\nBoth bioethanol and biodiesel have a poor oxidative stability, low energy content by volume, and high content of oxygenated compounds, which damage combustion engines and cause corrosion, erosion, and accumulation of deposits in the nozzles; because of these reasons, they are mixed with standard fuels [49, 50]. B. braunii accumulates hydrocarbons similar to those of the crude oil, and their direct contribution in the formation of oil reserves currently in use has been reported [3, 4, 5]. The B. braunii oils showed almost equal values in density and surface tension than the diesel, but with higher kinematic viscosity and distillation temperature [50]. The B. braunii race B oil was already converted into diesel with an 85% performance, using a simple conversion process under mild conditions of 260°C and 1 atm. The physical properties are relatively close to the specification for diesel, with 40 as estimated cetane (CN) number [51].
\nThe limitation to use B. braunii as biorefinery is the slow growth rate of days in comparison with hours in other algae [49, 52]. Other factors affecting the growth and hydrocarbon production are the strain, CO2, light, water, nutrients, temperature, pH, and salinity [53, 54, 55, 60] (Table 1). A JET PASTER treatment was used to do a mechanical cell disruption and removal of the polysaccharides of the B. braunii colonies, increasing the hydrocarbon extraction up to 82.8%. This treatment did not affect the photosynthetic function of the cells [56]. On the other hand, a repetitive nondestructive extraction with heptane was reported as having some advantages [57]. Also, a continuous growth and extraction column of n-dodecane was reported recently as an efficient hydrocarbon extraction method without significant loss of the viability of the cells [58]. Considering these milking procedures and achieving a 10% rate of return, a minimum sales price (MSP) of US$3.20 per liter was calculated, and a reduction down to US$1.45 per liter was proposed, if hydrocarbon content increases and extraction procedures become more efficient [59].
\nSt | \nCulture conditions | \nSCGR | \nDt | \nTHC | \nRef. | \n|||
---|---|---|---|---|---|---|---|---|
°C | \nPAR | \nPhp | \nCO2 | \n|||||
Showa (B) | \n30 | \n850 | \n14:10 | \n1 | \n0.5 | \n1.40 | \nNIA | \n[54] | \n
Showa (B) | \n25, 30 | \n85–398 | \n14:10 | \n1.0–10.0 | \n0.19–0.44 | \n1.60–3.60 | \n30–39 | \n[54] | \n
Showa (B) | \n23–25 | \n250 | \n24 | \n0.3 | \n0.42 | \n1.70 | \n24–29 | \n[52] | \n
Showa (B) | \n23 | \n150 | \n16:8 | \n2 | \n0.17 | \n4.08d | \n25 | \n[55] | \n
Yayoi (B) | \n25 | \n240 | \n12:12 | \n2 | \n0.2 | \n3.50 | \n40.5 | \n[38] | \n
AC759 (B) | \n23 | \n150 | \n16:8 | \n2 | \n0.07 | \n9.90d | \n21 | \n[55] | \n
AC761 (B) | \n23 | \n150 | \n16:8 | \n2 | \n0.11 | \n6.30d | \n45 | \n[55] | \n
IPE001 (B) | \n25 | \n35 | \n16:8 | \n1 | \n0.15c | \n4.50c | \n64.3 | \n[61] | \n
BOT-144 (B) | \n25 | \n60a | \n24 | \n0 | \n0.16 | \n4.33d | \n50 | \n[62] | \n
LB-572 (A) | \n26 | \n12 Klux | \n24 | \n2 | \n0.07c | \n10.60c | \n28 | \n[53] | \n
Gottingen 807/1 (A) | \n25 | \n26b | \n14:10 | \n1 | \n0.3 | \n2.30 | \n40.5 | \n[67] | \n
AC755 (A) | \n23 | \n150 | \n16:8 | \n2 | \n0.05 | \n13.86d | \n16 | \n[55] | \n
CCALA777 (A) | \n23 | \n150 | \n16:8 | \n2 | \n0.06 | \n11.55d | \n10 | \n[55] | \n
CCALA778 (A) | \n23 | \n150 | \n16:8 | \n2 | \n0.17 | \n4.08d | \n0 | \n[55] | \n
CCAp807/2 (A) | \n23 | \n150 | \n16:8 | \n2 | \n0.11 | \n6.30d | \n7 | \n[55] | \n
765 | \n25 | \n150 | \n24 | \n20 | \n0.13c | \n5.50c | \n24 | \n[64] | \n
765 | \n25 | \n120 | \n24 | \nASLW | \nNIA | \nNIA | \n23.8 | \n[65] | \n
GUBIOTJTBB1 | \n25 | \n35 | \n16:8 | \n0 | \n0.112 | \n6.19 | \n52.6 | \n[66] | \n
AP 103 | \n23 | \n30 | \n16:8 | \n0 | \nNIA | \nNIA | \n13 | \n[67] | \n
Comparison of culture conditions and productivity of hydrocarbons between B. braunii strains at laboratory scale.
ASLW, aerated swine lagoon wastewaters (not sterile); °C, temperature; CO2, % v/v; Dt, doubling time (days); NIA, no information available; PAR, photosynthetic active radiation (μmols of photons/m2 s); Php, photoperiod (light/dark hours); SCGR, specific cell growth rate (μ/day); μ, specific velocity of growth rate; St, strain (race); THC, total hydrocarbons (% DW, dry weight).
There are different open and closed culture systems in photobioreactors (PBR) [63, 64], but more studies are required at pilot and industrial scale, to reduce problems by contamination and low yield of biomass and hydrocarbon production [49]. Table 2 summarizes some data about cell growth and hydrocarbon productivity using different culture systems.
\nSt | \nSystem | \nCultures | \nBiomass | \nHCs | \nRef | \n|||||
---|---|---|---|---|---|---|---|---|---|---|
°C | \nPAR | \nCO2 | \nSCGR | \nXmax | \nPx | \nCNT | \nWHC | \n|||
GUBIOT JTBB1 | \nPlain (3 L) | \n25 | \n35 (16 h) | \n0% | \n0.112 | \nNIA | \n13 | \n52.6 | \n6.8 | \n[62] | \n
765 | \nColumn (3 L) | \n25 | \n150 (24 h) | \n20% | \n0.13g | \nNIA | \n92.4 | \n24.45g | \n22.6 | \n[64] | \n
Showa (B) | \nPBRa | \n25-28 | \n282 (15 h) | \n5–7% | \nNIA | \n20 | \n1500 | \n22.5 | \n225-340 | \n[68] | \n
NIA | \nPBRb | \n25 | \n270 (24 h) | \nMixo-trophic | \nNIA | \n4.55 | \n234 | \n29.7 | \n71.1 | \n[69] | \n
UTEX-LB 572 (A) | \nCircular (50 L) | \nrT | \nSol r | \n0% | \nNIA | \nNIA | \n77.8 | \n19 | \n13.2 | \n[70] | \n
N-836 (B) | \nRcwy (80 L) | \nrT | \nSol r | \n0% | \nNIA | \nNIA | \n40 | \n24 | \n10.8 | \n[70] | \n
LB572 (B) | \nPBRc | \n20 | \nSol r | \n0% | \n0.04 | \n0.3 | \n15 | \nNIA | \n2.4 | \n[71] | \n
AP103 | \nRcwy (1800 L) | \n29 | \nSol r 5 kWh/m2.day | \n0% | \n0.38 | \nNIA | \n114 | \n11 | \n12.5 | \n[67] | \n
UTEX-LB 572 (A) | \nPBRd | \n25 | \n55 (24 h) | \n1% | \nNIA | \n96.4 | \n0.71i | \nNIA | \nNIA | \n[72] | \n
FACHB 357 (B) | \nAttchde | \n25 | \n500 (24 h) | \n1% | \nNIA | \n62h | \n5.5–6.5i | \n19.43 | \n1.06i | \n[73] | \n
TN101 | \nRcwy scf | \nrT | \nSol r | \n0% | \nNIA | \nNIA | \n33.8i | \n22.6 | \n8.2-13i | \n[74] | \n
Comparison of culture conditions and productivity of hydrocarbons between strains of B. braunii in bioreactors.
“Tickle film” (30.5 × 16.5 in) continuous.
"Airlift" (10 L).
Panel (1000 L) outdoor and semicontinuous.
"Biofilm" (0.275 m2 or 600 mL).
“Attached” bioreactor (0.08 m2 or 240 mL).
(25 m2 or 5000 L) semicontinuous.
Estimated values [64].
g/m2.
g/m2/day; shadow area indicates the highest reported values up to now.
°C, temperature; CNT, content (% DW dry weight); CO2, % v/v; HCs, hydrocarbons; PAR, photosynthetic active radiation (μmols of photons/m2 s); PBR, photobioreactor; Php, photoperiod (light/dark hours); Px, biomass productivity (mg/L day); NIA, no information available; Rcwy, raceway; rT, room temperature; SCGR, specific cell growth rate (μ/day); μ, specific velocity of growth rate; Sol r, solar radiation; St, strain (race); WHC, weight of hydrocarbons (mg/L day); Xmax, maximum cellular concentration (g/L).
B. braunii also produces saturated and monounsaturated fatty acids, especially palmitic (16:0) and oleic (18:1), as well as triacylglycerols (TAGs). The percentages of total lipids as saturated, monounsaturated, and polyunsaturated fatty acids in dry biomass are around 44.97, 9.85, 79.61, and 10.54%, respectively [64, 75]. Studies in vitro and in vivo showed that these fatty acids effectively improve the absorption of lipophilic drugs like flurbiprofen, through the skin [76].
\nB. braunii stores TAGs and saturated fatty acids in the lag phase as an adaptation to stress conditions but most are synthesized during the stationary phase. Although highest content of these acids is intracellular, B. braunii secretes oily drops in small quantities observed on the surface of the cell apex [64].
\nThe yield and lipid composition depends on the strain, the culture system used, growth conditions and cell aging, as well as nitrogen, phosphorus, and micronutrient concentrations (Table 3).
\nSt | \nSystem | \nTRT | \nBiomass | \nLipids | \nRef. | \n||||
---|---|---|---|---|---|---|---|---|---|
SCGR | \nXMax | \nPx | \nCNT | \nYld. | \nProd. | \n||||
UTEX 572 (A) | \nEF (125 mL) | \n0.04 mM NO3 | \n0.09 | \n0.16 | \nNIA | \n63 | \nNIA | \n0.009 | \n[77] | \n
0.37 mM NO3 | \n0.185 | \n0.38 | \nNIA | \n36 | \n0.19 | \n0.019 | \n|||
KMITL 2 (n.d.) | \nEF (1 L) | \n86 mg/L NO3 | \nNIA | \n0.48 | \nNIA | \n39.42 | \n0.19 | \nNIA | \n[78] | \n
222 mg/L PO4 | \nNIA | \n0.86 | \nNIA | \n54.69 | \n0.47 | \nNIA | \n|||
444 mg/L PO4 | \nNIA | \n1.91 | \nNIA | \n23.23a | \n0.45 | \nNIA | \n|||
27 mg/L Fe | \nNIA | \n0.22 | \nNIA | \n34.93 | \n0.08 | \nNIA | \n|||
KMITL 2 (n.d.) | \nOutdoor oval pond (150 L) | \n0.17 g/L NO3 | \n0.045 | \n4.84 | \nNIA | \n35.24 | \nNIA | \n0.016 | \n[79] | \n
2.5 g/L NO3 | \n0.049 | \n5.62 | \nNIA | \n38.60 | \nNIA | \n0.0189 | \n|||
LB572 (A) | \nFBR column (625 mL) | \n0083 g/L PO4 and 0.1 g/L SO4 | \nNIA | \nNIA | \n0.296 | \n64.96 | \nNIA | \n0.19 | \n[80] | \n
0058 g/L PO4 and 0.09 g/L SO4 | \nNIA | \nNIA | \n0.304 | \n59.56 | \nNIA | \n0.18 | \n|||
TRG | \nEF (250 mL) | \nPhotoaut. (CO2) | \n0.093 | \n1.14 | \nNIA | \n25.1 | \nNIA | \n0.0241 | \n[81] | \n
Heterot. (gluc 5 g/L) | \n0.115 | \n1.75 | \nNIA | \n29.3 | \nNIA | \n0.0467 | \n|||
Mixot. (gluc 5 g/L + CO2) | \n0.195 | \n2.46 | \nNIA | \n37.5 | \nNIA | \n0.0645 | \n|||
IBL-C117 | \nEF (1 L) | \nChu (0.75×) | \n0.13 | \n0.9 | \n0.12 | \n47.1 | \nNIA | \nNIA | \n[82] | \n
Chu (1.0×) | \n0.13 | \n0.7 | \n0.1 | \n46 | \nNIA | \nNIA | \n|||
Chu (2.0×) | \n0.11 | \n1 | \n0.15 | \n41.3 | \nNIA | \nNIA | \n|||
LB572 (A) | \nEF (1 L) | \nChu (0.75×) | \n0.15 | \n1.3 | \n0.18 | \n20.2 | \nNIA | \nNIA | \n[82] | \n
Chu (1.0×) | \n0.16 | \n1.4 | \n0.2 | \n22.5 | \nNIA | \nNIA | \n|||
Chu (2.0×) | \n0.17 | \n1.5 | \n0.22 | \n11 | \nNIA | \nNIA | \n|||
2441 (A) | \nFBR Airlift (2 L) | \n(N:P = 1:1) in Chu | \nNIA | \n4.963 | \n0.173 | \n33.7 | \nNIA | \nNIA | \n[83] | \n
(N:P = 3:3) in Chu | \nNIA | \n3.857 | \n0.215 | \n34.6 | \nNIA | \nNIA | \n|||
(N:P = 6:6) in Chu | \nNIA | \n3.987 | \n0.223 | \n32.1 | \nNIA | \nNIA | \n|||
BOT22 (B) | \nBiofilm bioreac. | \nNitrocell. Memb. (diam. 25 mm and pore size 0.45 μm) | \nNIA | \n3.12a | \n0.42b | \nNIA | \n0.83a | \nNIA | \n[84] | \n
BOT84 (L) | \nNIA | \n10.04a | \n3.8b | \nNIA | \n1.11a | \nNIA | \n|||
BOT7 (S) | \nNIA | \n13.6a | \n0.99b | \nNIA | \n0.83a | \nNIA | \n
Comparison of crop conditions and lipid productivity in B. braunii.
mg/cm2.
mg/cm2/day.
CNT, content (% DW dry weight); Chu, Chu media for microalgae [8]; EF, Erlenmeyer flask; FBR, photobioreactor; N:P, proportion of nitrogen: phosphate; Px, biomass productivity (g/L day); NIA, no information available; Prod., productivity (g/L day); Rcwy, raceway; SCGR, specific cell growth rate (μ/day); μ, specific velocity of growth rate; St, strain (race); TRT, treatment; Yld., yield (g/L); Xmax, maximum cellular concentration (g/L).
Algae pigments have been reported to have antioxidant, anticancer, anti-inflammatory, antiobesity, and antiangiogenic properties and function as neuroprotectives [85]. So, they could replace synthetic dyes in food, cosmetic, nutraceutical, and pharmaceutical products [86].
\nCarotenoid pigments are unsaturated hydrocarbons, while xanthophylls have one or more functional groups containing oxygen such as lutein, canthaxanthin, and astaxanthin [85, 86, 87].
\nCarotenoids abound in races B and L, lutein being the main pigment (22–29%), followed by others as β-carotene, echinenone, 3-OH echinenone, canthaxanthin, violaxanthin, loroxanthin, and neoxanthin. Transition to stationary phase causes a color change in B. braunii from green to brown, reddish orange, and pale yellow by accumulation of carotenoids and a decrease of intracellular pigments [88]. Canthaxanthin (46%) and echinenone (20–28%) are predominant in the stationary phase in response to nitrogen deficiency [36]. The BOT-20 strain showed a dark red color during growth because of the accumulated echinenone of about 30.5% dry weight and 630 mg/L production, but with few hydrocarbons (8%) [89].
\nAdonixanthin was detected in race L during the stationary phase [90], and botryoxanthin A, botryoxanthin B, and braunixanthin 1 and 2 were detected in race B [37, 38, 91]. The 2-azahypoxanthine (AHX) similar to the phytohormone induced the accumulation of secondary carotenoids like botryoxanthin A and braunixanthin 1 and decreased the content of botryococcenes during the stationary phase [92], imitating a lack of nitrogen condition without inhibiting the growth.
\nIn race A, lutein (79–84%) is the main carotenoid followed by β-carotene (1.75–2.14%), violaxanthin (6–9%), astaxanthin (3–8%), and zeaxanthin (0.32–0.78%). In salinity and high light intensity conditions, the lutein increases [53, 93]. All of these compounds shown antioxidant properties and inhibitory effect against lipid peroxidation in vitro and in vivo and activated antioxidant enzymes such as catalase [94, 95].
\nThe aqueous extracts of B. braunii (strain LB 572) reduce the skin dehydration, stimulate collagen synthesis, promote the differentiation of adipocytes, and promote antioxidant and anti-inflammatory activities [96]. The extracellular polysaccharides (exopolysaccharides, EPS) constitute most of the organic material of high molecular weight released to the environment by microalgae and other microorganisms. They have antioxidant, immunomodulatory, antibacterial, antiviral, anticarcinogenic, and antihypocholesterolemic effects [97]. They are used as thickeners, emulsifiers, bioflocculants, stabilizers, and gelling agents in foods and cosmetics; are soluble in water; and modify the rheological properties of solutions increasing their viscosity to form gels [1, 98].
\nThe ECM and the fibrillar pod are composed of mucilaginous polysaccharides [20], and other detected EPS are fucose, glucose, mannose, rhamnose, uronic acids, and unusual sugars such as 3-O-methyl fucose, 3-O-methyl rhamnose, and 6-O-methyl hexose [1]. Galactose is involved in the innate and adaptive immune system [99].
Some B. braunii (UC 58) strains produce 4.0–4.5 g/L EPS with few hydrocarbons (5%). The EPS amount varies with the strain, race, physiological conditions, and culture. Strains of A and B races can produce up to 250 mg/L EPS, and race L up to 1 g/L plus glucose [1].
\nGreater EPS production correlates with minor growth by N deficiency. Urea and ammonia decrease the pH, as well as EPS production. Optimal conditions for EPS production were nitrate (8 mM) and between 25 and 30°C. Out of these temperatures, the EPS polymerization decreased significantly [1, 102]. Light/dark (16:8) photoperiod produced more hydrocarbons, but continuous light with agitation increased EPS until 1.6 and 0.7 g/L in LB 572 and SAG-30 strains, respectively [103]. EPS production increased (2–3 g/L) in low salinity levels (17–85 mM) as osmoprotectants [53]. High salinity and low N content in D medium induced EPS production (0.549 ± 0.044 g/L) in comparison to the BG11 medium (0.336 ± 0.009 g/L), but biomass was higher in BG11 (1.019 ± 0.051 g/L) than in D (0.953 ± 0.056 g/L) [104]. Modification of culture conditions could be used to increase EPS production, to facilitate the removal, and to increase hydrocarbon recovery. With Botryococcus braunii CCALA 778 (race A), a light:dark cycle at 26°C resulted in an increased production of EPS, and a milking procedure for these polysaccharides has been proposed [105, 106]. EPS can be used as thickening or gelling agents [107].
\nAlgenanes are aliphatic, nonhydrolyzable, and insoluble biopolymers found in the ECM at 9 and 10% dry weight of race A and B, respectively. Due to their high resistance to degradation, they are attributed to the good preservation of colonies in sedimentary rocks [108].
\nAnother reported biopolymer was the polyhydroxybutyrate (PHB), a biodegradable plastic with a yield of about 20% of the dry weight [109]. PHB is a polyester with thermoplastic and biodegradable properties, and it\'s a carbon and energy storage compound. For its similar physical properties to polypropylene and polystyrene, it is of commercial interest [110]. Under pH 7.5, 40°C, and with 60% wastewater as culture medium, a maximum yield of 247 ± 0.42 mg/L PHB was reported [111].
\nB. braunii (UTEX 572) was used to produce intra- and extracellular Ag nanoparticles (AgNPs) with antimicrobial properties, and analysis suggested that the exopolysaccharides were the possible reducing and capping agents [112].
\nAlthough B. braunii has been considered mainly as a good source of biofuels by the possibility to convert its hydrocarbons into currently used fuels, without the necessity of engine modifications, it produces many other high-value derivatives that can be exploited for their promising attractive profits. Besides, along the photosynthetic process, this alga converts 3% of solar energy into hydrocarbons [1] and can reduce CO2 emissions up to 1.5 × 105 tons/year [113]. There are several reports about modifications of the culture conditions through vitamin addition, affecting the yield of several derivatives like biomass, hydrocarbon, and carbohydrate in Botryococcus braunii KMITL 5 [114]; however, those are from not clearly recognized strains and should be carefully taken. With B. braunii race A, B, or L, the main challenge is to accelerate the doubling rate because, depending on the race, it varies between 2 and 10 days. This results in easy contamination with faster growing microorganisms in open ponds used for industrial production, or a high cost of sterile conditions in closed bioreactors. In spite of these disadvantages, we consider that B. braunii is an excellent model of biorefinery. Other strategies to use B. braunii as biorefinery and bioreactor are being developed like the immobilization in polyester [115] or bioharvesting with Aspergillus sp. [116].
\nTo the Consejo Nacional de Ciencia y Tecnología (CONACYT) Mexico by the PhD and MSc scholarships of XM-dlC and TAO-U respectively.
\nThe authors declare no conflict of interest.
Authors are listed below with their open access chapters linked via author name:
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\\n\\nXin-She Yang 2017, 2018
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