Potential plant-bioactive compounds that interact with microtubules as microtubule-destabilizing agents for cancer therapy.
In this overview we describe the main plant-derived bioactive compounds used in cancer therapy which has the cell cytoskeleton as therapeutic target. Three major classes of these compounds are described: antimitotics with microtubule-destabilizing and—stabilizing effects, plant-bioactive compounds that interact with intermediate filaments/actin, and plant-bioactive compounds that interact with intermediate filaments like keratins and vimentin. We also focus on the molecular aspects of interactions with their cellular targets: microtubules, intermediate filaments, and microfilaments. Some critical aspects of cardiac side effects of cancer chemotherapy are also discussed, focusing on cardiac cytoskeleton and protective effect of plant-derived compounds. The application of plant bioactives in the treatment of cancer has resulted in increased therapeutic efficacy through targeting the cytoskeleton, respectively, prevention of the injury of cytoskeletal components elicited by chemotherapeutics.
- plant-derived compounds
- cancer therapy
- intermediate filaments
Chemotherapy is routinely used for cancer treatment. Since tumor cells lose many of the regulatory pathways of the normal cells, they continue to divide without control. Chemotherapeutic drugs try to solve these abnormalities, but sometimes the toxicity of allopathic treatments creates a significant problem.
The cytoskeleton constitutes the supporting framework of the cell, and it is composed of three types of cytosolic filaments: microtubules, intermediate filaments, and microfilaments. The entire cytoskeletal network is a dynamic structure which regulates the cell structure, and it is involved in many cellular functions such as movement, transport, or cell division . The cytoskeleton is one of the main therapeutic targets in cancer cells .
Various cancer therapies use plant-derived bioactive products. There are four classes of plant-derived anticancer drugs currently used in oncotherapy: vinca alkaloids (vinblastine, vincristine), epipodophyllotoxins (etoposide and teniposide), taxanes (paclitaxel and docetaxel), and camptothecin derivatives (camptothecin and irinotecan) . To date, new generations of vinca alkaloids, camptothecins, and epothilones as well as a novel class of taxanes have been developed. Some of these are in clinical use, others in clinical trials.
The major inconvenience in using antimicrotubule agents in oncotherapy is that these compounds cause significant side effects such as neutropenia and neurotoxicity and because of their limited efficacy as single agents .
This review describes the main natural compounds identified in the last year as potential anticancer agents, which have cell cytoskeleton as therapeutic target. We focus on the interactions of plant-derived anticancer drugs with all three types of cytosolic filaments: microtubules, intermediate filaments, and microfilaments. In addition, we summarize the most recent advances in the understanding of the molecular aspects of these interactions.
Some critical aspects of cardiac side effects of cancer chemotherapy are also discussed, focusing on cardiac cytoskeleton and protective effects of plant-derived compounds.
2. Microtubules as chemotherapeutic targets of plant-derived bioactives
Microtubules are dynamic structures involved in different cellular processes including cell division, where they are the most important constituents of the mitotic spindle apparatus during the M phase of cell division . They are polymers composed of α- and β-tubulin heterodimers, characterized by high dynamics of polymerization/depolymerization, resulting in the elongation or shrinkage of the filaments. Polymerization of microtubules occurs when α- and β-tubulin monomers bind to a GTP at the nucleotide exchangeable site (E-site) in β-tubulin and the non-exchangeable site (N-site) in α-tubulin. Once GTP is hydrolyzed, it becomes non-exchangeable, which matches the addition of the next tubulin dimer to the plus (+) end of the microtubule. Upon depolymerization, the GTP cap is detached, allowing the microtubules depolymerize releasing the α-/β-tubulin heterodimers into the cytoplasm. Subsequently, the GDP attached to another free β-tubulin and can exchange to GTP at the E-site, before another polymerization cycle begins [4, 5].
Dynamic instability is regulated by a number of microtubule-associated proteins (MAPs), which bind to stabilize the microtubules . MAP phosphorylation induces its dissociation leading to microtubule instability. Some cytokines have a critical role in the regulation of MAPs and microtubule dynamics, such as controlling centromere localization Cdc2 kinases, mitogen-activated protein kinases ERK, controlling cell migration JNK, and the main serine/threonine phosphatases, type 1 (PP1) and type 2A (PP2A) [7–10].
The dynamic ability of microtubules to polymerize and depolymerize is essential for cellular division and chromosome segregation during mitosis. Due to their crucial roles in dividing cells, microtubules have been considered a major target for cancer therapy. Microtubule-interacting plant-derived biomolecules, namely, antimitotics, can be classified into two main groups based on their apparent mechanisms of action: microtubule-destabilizing agents act as tubulin polymerization inhibitors, and microtubule-stabilizing agents act as tubulin polymerization promoters .
2.1. Microtubule-destabilizing agents
Vinca alkaloids and colchicines prevent the polymerization of tubulin and promote the depolymerization of microtubules.
Vinca alkaloids are a series of biologically active agents isolated from
The vinca alkaloids are dimeric compounds consisting of two multi-ringed subunits, vindoline and catharanthine, linked by a carbon-carbon bridge . They act by binding specifically to β-tubulin and block its ability to polymerize with α-tubulin into microtubules, thus disrupting the mitotic spindle. This blocks mitosis and kills actively dividing cells. The results indicate that vinorelbine and vinflunine affect microtubule dynamics differently from vinblastine and proved to be weak binders .
Vincristine is used in the treatment of hematological and lymphatic neoplasms, whereas vinblastine in breast cancer, testicular cancer, choriocarcinoma, and vindesine in non-small cell lung cancer or breast cancer. Vinorelbine is useful for the treatment of non-small-cell lung cancer, and vinflunine has been used in the treatment of bladder, non-small-cell lung, and breast cancers .
Similar to Vinca alkaloids, colchicine extracted from plants of the genus
Novel microtubule-destabilizing plant-bioactive compounds are summarized in Table 1.
|Active substance/herbal formulation||Mechanism of action||Therapeutic use||References|
|Flavonoids isolated from ||—Modulate microtubule depolymerization by activating mitotic spindle checkpoint|
—Bind at α- β interfacial site of tubulin
|Artelastin isolated from the wood bark of ||—Radial structure disorganization of the microtubule network|
—Kinetochores are not affected
|Podoverine A isolated from ||—Mitotic arrest and inhibition of microtubule polymerization by targeting the vinca-binding site on tubulin||Renal cancer|
|Plinabulin chemical probe KPU-244-B3||—Binds in the boundary region between α- and β-tubulin near the colchicine-binding site|
—Induce tubulin depolymerization
|2′-Hydroxy-2,4,6-trimethoxy-5′,6′-naphthochalcone||—Disruption of microtubular networks by inhibition of tubulin polymerization|
—Failure of mitotic spindle formation and blocking mitosis at the prometaphase or metaphase-anaphase transition
|Aqueous extract of ginger||—Disruption of interphase microtubule network of A549 and HeLa cells|
—Inhibition of temperature-dependent reassembly of cold-treated depolymerized microtubule of A549 and HeLa cells
|Safranal||—Inhibition of tubulin assembly (IC50 was obtained at 72.19 µM)|
—Binds between α- and β-tubulin closer to alpha-tubulin and hydrogen bond with Gly 142
—Hydrophobic interactions play critical roles for safranal molecule stabilization in binding site
|Isochaihulactone||—Inhibition of tubulin polymerization in a concentration-dependent manner in A549 non-small-cell lung cancer cells|
—Cause G2/M phase arrest and apoptosis in a time- and concentration-dependent manner
|Carnosol||—Modulation of autophagic markers microtubule- associated protein 1A/1B light-chain 3 I (LC3 I) to microtubule- associated protein 1A/1B light-chain 3 II (LC3 II) and p62 in MDA-MB-231 cells||Breast cancer|||
|Angelica shikokiana methanol extract (AME)||—AME and all isolated compounds inhibited tubulin polymerization|
—Angelicin and kaempferol-3-O-rutinoside were the most active compounds
—Phenolic compounds and furanocoumarins showed binding affinity to colchicine-binding site
—Quercetin, kaempferol, luteolin, chlorogenic acid, and methyl chlorogenate exhibited the strongest activity against histone deacetylase 8 (HDAC8) and the highest affinity to trichostatin A-binding site.
|Human hepatocellular carcinoma, rhabdomyosarcoma (RD), colorectal carcinoma, human epithelioma, and human breast adenocarcinoma|||
|Alkaloids from beach spider Lily (||—Interrupt polymerization of microtubules in Hep-G2 cells||Hepatocarcinoma|||
|DYZ-2-90||—Binds to microtubules and rapidly induces tubulin depolymerization||Colorectal cancer|||
|Indicine N-oxide (INO)||—200 µM induced a mitotic block of about 22% in HeLa cells; 300 µM concentration-induced depolymerization of interphase microtubular network|
—The effect was similar to the depolymerizing effects of the drugs such as colchicine and vinblastine, although the concentration used here was 1000-fold higher than those drugs
—Binds to the tubulin dimer through hydrogen bonds and hydrophobic interactions
—INO does not make any interactions with the amino acid residues on the tubulin dimer that were reported to be interacting with the taxol or colchicine, but INO-binding site partially overlaps with the griseofulvin-binding site (docking)
2.2. Microtubule-stabilizing agents
Taxanes are the main class of microtubule-stabilizing agents, which prevent the depolymerization of microtubules and promote the polymerization of tubulin to microtubules.
One of the most important plant compounds in the fight against cancer was discovered in the bark of
Initially obtained from
Docetaxel has a 1.9-fold higher affinity for the site than paclitaxel and induces tubulin polymerization at a 2.1-fold lower critical tubulin concentration. The effect on the cell cycle is different: paclitaxel inhibits the cell cycle traverse at the G2/M phase junction , while docetaxel produces its maximum cell-killing effect against cells in the S phase .
To decrease the toxicity and enhance delivery and distribution, new taxane formulations of micelles were investigated, including nanoparticles, emulsions, and liposomes . Com-pounds such as Abraxane, CT-2103, and docosahexaenoic acid (DHA)-paclitaxel are examples of new taxanes with higher activity than paclitaxel in taxane-resistant cancers, as well as in tumors that have been unresponsive to paclitaxel .
Protopine is a benzylisoquinoline alkaloid isolated from
Taccalonolides are plant steroids possessing a C2–C3 epoxide group and an enol-lactone isolated from
Recent study shows that the dietary flavonoid fisetin binds to tubulin and stabilizes microtubules with binding characteristics far superior than paclitaxel. It induces upregulation of microtubule-associated protein (MAP)-2 and microtubule-associated protein (MAP)-4 and increases α-tubulin acetylation, an indicator of microtubule stabilization .
3. Microfilaments as chemotherapeutic targets of plant-derived bioactives
Actin filaments are composed of globular actin (G-actin) which polymerizes into filamentous (F) actin and participates in many important cellular processes including cell division and cytokinesis, cell signaling, vesicle and organelle movement, cell junction establishment, and maintenance.
Like microtubules, actin microfilaments can change rapidly their structure in response to external stimuli. Actin polymerization is stimulated by nucleating factors such as the Arp2/3 complex, which mimics a G-actin dimer in order to stimulate actin polymerization . Actin binds ATP to stabilize microfilament formation and hydrolysis . The growth of microfilaments is regulated by thymosin, which binds G-actin to lead the polymerizing process, whereas profilin binds G-actin and catalyzes the exchange of ADP to ATP, promoting monomeric addition to the plus end of F-actin .
During cytokinesis, disruption of actin polymerization can effect cellular structure. Cytoki-nesis inhibitors such as cytochalasin B disrupt the actin cytoskeleton, and the cell is unable to divide  but is still able to initiate another mitotic event, continuing to form nuclei and eventually becoming enlarged and multinucleated [55, 56]. Cell lines derived from bladder, kidney, and prostate carcinomas become multinucleated when grown in cytochalasin B-supplemented medium, whereas cells from corresponding normal tissue remain mono- or binucleate under comparable conditions . These particular features make tumor cells ideal targets for chemotherapy, as they have reduced cytoskeletal integrity and multiple nucleation and increased mitochondrial activity .
Actin filaments are also of substantial importance to cancer cell migration. Cancer cell migration can convert between mesenchymal and amoeboid types. This latter can occur, e.g., when cells are exposed to protease inhibitors  and thereby mesenchymal cancer cell invasion is repressed by specific targeting of protease function. Inhibiting RhoA/ROCK signaling promotes the formation of multiple competing microfilament-derived lamellipodia that suppress amoeboid migration of tumor cells . Tumor cells unable to move through amoeboid migration will switch to mesenchymal migration . However, tumor cells exposed to protease inhibitors will move mainly through amoeboid migration. Using microfilament disrupting RhoA/ROCK inhibitors in combination with protease inhibitors would simultaneously block both types of cell migration.
Phytomedicine developed actin-targeted potential drugs, designed for cancer therapy (Table 2).
|Active substance/herbal formulation||Mechanism of action||Therapeutic use||References|
|Resveratrol||—50 µM resveratrol decreases Rac and Cdc42 signaling to the actin cytoskeleton|
—5 µM resveratrol increases Rac signaling to the actin cytoskeleton
|Oleuropein||—Disrupt actin filaments in a dose-dependent manner||Sarcoma|||
|Alkaloid mixture derived from ||—Altered normal distribution pattern of F-actin filaments||Liver cancer|||
|Deoxyelephantopin (DET)||—Affects the actin cytoskeleton network and downregulates calpain-mediated proteolysis of several actin-associated proteins|
—Inhibition of proteolysis of actin cytoskeleton-associated proteins identified by differential proteomic profiling
|Lung metastasis of mammary adenocarcinoma|||
|Cucurbitacin E||—Disruption of the F-actin cytoskeleton|
—Increases the filamentous or polymerized actin fraction
|Prostate carcinoma cells|||
|Cucurbitacin E||—Damaged F-actin without affecting beta-tubulin||95D lung cancer cells|||
|Cucurbitacin I||—Induced the co-aggregation of actin with phospho-myosin II by stimulation of the RhoA/ROCK pathway and inhibition of LIM-kinase||HeLa cells|||
|Cucurbitacin B||—Induced rapid and improper polymerization of the F-actin network||Myeloid leukemia cells|||
|Jasplakinolide (JAS)||—Rearranged the actin cytoskeleton|
—JAS has a phalloidin-like action
—Distribution of actin filaments was different from that induced by cytochalasin D
|—Inhibits growth and induce actin polymerization||Bladder cancer cells|||
|4-Hydroxycoumarin||—Disorganized the actin cytoskeleton correlated with reductions in cell adhesion to four extracellular matrix proteins and inhibition of random motility||Melanoma cell line B16–F10|||
4. Intermediate filaments as chemotherapeutic targets of plant-derived bioactives
Along with microfilaments and microtubules, intermediate filaments are the other component of the cytoskeleton that can be exploited in the clinical treatment of cancer. All intermediate filaments have a central alpha-helical domain that is composed of four protofibrils separated by three linker regions . The N- and C-terminus segments of intermediate filaments are non-alpha-helical regions of polypeptide sequences, associated with head to tail into protofilaments that pair up laterally into protofibrils; four of these protofibrils form an intermediate filament.
Whereas microfilaments and microtubules are actin or tubulin polymers, intermediate filaments are composed of 50 different proteins classified into six types based on similarities in amino acid sequence . In regard to potential chemotherapeutic targets, the most promising intermediate filaments are keratins, nestin, and vimentin.
4.1. Anti-keratin agents
Keratin and cytokeratin are intermediate filaments found in the cytoskeleton of epithelial tissue. There are twenty different keratin polypeptides (K1–K20) identified and classified into type I (K9–K20) and type II (K1–K8) intermediate filaments . Keratins of importance to cancer therapy are keratin 8 (K8) and keratin 18 (K18), the most common and characteristic members of intermediate filaments expressed in single-layer epithelial tissues [74, 75]. Oncogenes, which activate Ras signaling, stimulate expression of K18 through transcription factors . However, aberrant K8 and K18 expression has been noticed in particularly invasive carcinomas [77, 78]. K18 was found to be a substrate of the cysteine-aspartic proteases during epithelial apoptosis .
Based on aberrant keratin expression found in many cancers, these intermediate filaments present a novel chemotherapeutic target that need to be investigated.
Crude acetone extract of
4.2. Anti-vimentin agents
Vimentin functions as a regulator in cancer cells undergoing epithelial-mesenchymal transition (EMT), an important change during tumor progression where cells detached from their original tissue become highly motile and invasive. Studies have shown that quercetin prevented epidermal growth factor (EGF)-induced EMT, migration, and invasion of prostate cancer cells by suppressing the expression of vimentin and N-cadherin . Genistein, an isoflavone found in soybeans, fava beans, and lupine, has been shown to downregulate mesenchymal markers ZEB1, slug, and vimentin and therefore cause reversal of EMT in gemcitabine-resistant pancreatic cancer cells . Similarly, this flavonoid was able to decrease protein expression of vimentin, cathepsin D, and MMP-2 and thus suppressed epithelial-mesenchymal transition and migration capacity of BG-1 ovarian cancer cells . Other natural compounds, like silibinin, induced the morphological reversal of mesenchymal phenotype to epithelial phenotype through downregulation of vimentin and MMP-2 and upregulation of cytokeratin-18 . Moreover, silibinin meglumine, a water-soluble form of milk thistle silymarin, impedes the EMT in EGFR-mutant non-small-cell lung carcinoma cells by upregulation of the relative mRNA expression of CDH1 (E-cadherin) accompanied by downregulation of vimentin . Berberine, a plant alkaloid present in various plants like
Piplartine, a biologically active component from
Phenethyl isothiocyanate (PEITC), the main bioactive compound present in cruciferous vegetables, decreases breast and prostate tumor growth inhibition through vimentin suppression . Cucurbitacin E induced disruption of vimentin cytoskeleton in prostate carcinoma cells, while microtubules were unaffected . The natural product withaferin A (WFA) exhibits antitumor activity by binding to vimentin and covalently modifying its cysteine residue, which is present in the highly conserved helical coiled coil 2B domain . Penduletin and casticin, flavonoids from the Brazilian plant
5. Protective effect of plant-bioactive compounds on anthracycline-induced cardiac cytoskeletal toxicity
Cardiotoxicity is the most serious side effect of antitumoral anthracyclines, which include adriamycin, doxorubicin, mitoxantrone, daunorubicin, or epirubicin . The main cause of toxicity is their effect on the cardiac cytoskeleton, consisting of myofibrils disarray , including both structural and functional changes: troponin I and troponin C phosphorylation mediated by a doxorubicin-induced protein kinase C activation [92, 93] and decrease of troponin I, and changes of α-actin, creatine kinase, and myosin light-chain 2 expression . In other studies, degradation of cardiac cytoskeletal proteins, including titin  and dystrophin , was observed. Recently, changes in the cardiac distribution of desmin have been detected, with areas of decreased expression in the cytoplasm and protein aggregation after mitoxantrone treatment [96, 97]. The use of plant bioactives might protect against the oxidative stress caused by anthracycline drugs, including cytoskeleton injuries. Our group recently demonstrated that the flavonoid chrysin inhibits mitoxantrone-triggered cardiomyocyte apoptosis via multiple pathways, including decrease of the Bax/Bcl-2 ratio and caspase-3 expression along with preservation of the desmin disarray .
Plant-derived bioactive molecules constitute promising tools for the treatment of cancer. The application of plant bioactives in the treatment of cancer has resulted in increased therapeutic efficacy through targeting the cytoskeleton and prevention of cytoskeletal injuries due to chemotherapy side effects. Research results testify both the evolution of knowledge coming from pharmacognosy and the great possibilities of future progress by means of a rational approach of natural product-based drug discovery or new pharmaceutical formulations.
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