Chinese herbal medicines that induce intrinsic apoptosis in human cancer.
The high incidence of cancer is a global burden. Cancer cells acquire immortality, which results in loss of control in cell proliferation and population expansion. Cancer cells undergo a series of genomic instability, leading to mutated amplification or deletion of certain genes that strictly control the cell fate. Programmed cell death is a mechanism of cell fate control that is aberrantly regulated in cancer cells. Apoptosis is the major form of programmed cell death regulated by both intrinsic and extrinsic pathways. Discovering effective and specific alternative solutions that can reprogram apoptosis in cancer cells is always a challenge. Chinese herbal medicine has captured increasing attention from both researchers and manufacturers, as evidenced by observable curative effects from previous clinical experience. Hence, to clarify and reinforce the understanding of the effect of Chinese medicine on cancer, in this chapter, we will retrospectively review the latest 5 years of literature and summarize the mode of action of Chinese herbal medicine on apoptotic cell death in cancer. Both Chinese medicine-induced intrinsic and extrinsic mechanisms of apoptosis will be discussed, and common compounds from Chinese medicine with druggable potential as novel apoptosis-inducing agents will be highlighted.
- cell apoptosis
- Chinese herbal medicine
- programmed cell death
- intrinsic and extrinsic pathways
- human cancer
Programmed cell death is a tight process mediated by an intracellular program, whereby damaged or harmful cells and their organelles are recycled or disposed of. The regulated cell death occurs along with morphological alterations. Biologists have employed such morphotypes from functional and biochemical perspectives to classify cell death routines. As provided by the Nomenclature Committee on Cell Death, three major widely accepted definitions of terms include apoptosis, autophagy, and necrosis . Among them, apoptosis involves plasma membrane blebbing, cytoplasmic shrinkage, nuclear fragmentation, and chromatin condensation. The process ends up with formation of apoptotic bodies that are being taken up by phagocytic cells . Apoptosis has been orchestrated in detail as two basic mechanism-oriented classifications: intrinsic pathway and extrinsic pathway.
Intrinsic apoptosis is initiated by multiple exogenous and endogenous stimuli such as stress, DNA damage, and chemotherapy, whereby cytochrome c is increasingly released from the mitochondria to the cytosol. Irreversible mitochondrial outer membrane permeabilization (MOMP) hence occurs, followed by caspase-3 activation that mainly promotes the typical apoptosis features . In striking contrast, extrinsic apoptotic pathway is a modality of cell death driven by extracellular microenvironmental perturbations, which are normally two types of plasma membrane receptors: (1) death receptors consisting of a type of tumor necrosis factor (TNF) receptor FAS and TNF-related apoptosis-inducing ligand (TRAIL) receptors. The activation occurs when they bind to the cognate ligands; (2) dependence receptors such as NTN1, whose presence of elevated level relies on the drop in the levels of their specific ligands below a specific threshold. The process is then propagated by caspase-8 and executed mainly by caspase-3  (Figure 1).
To our knowledge, programmed cell death provides an important function in metazoan cells to eliminate the toxic accumulation of superfluous cells and organelles and thereby to sustain the homeostatic cellular life. Due to loss of control of cancer cells in proliferation and expansion, a major focus has been placed on the association between defective regulation of apoptosis and immortality property of cancer cells. A large body of experimental evidence has unveiled that the defect in the physiological mechanism of apoptosis may promote tumorigenesis, while regulated apoptosis contributes to the recovery from diseases. For example, MOMP is one of the most common phenomena observed which is mediated by a variety of protein interactions of B-cell lymphoma 2 protein (Bcl-2) family, representing a total of 25 pro- and anti-apoptotic proteins. During the life of the cell, the balance of Bcl-2 family proteins partly determines cellular health. Besides the presence of decreased levels of pro-apoptotic proteins, the activation of anti-apoptotic family members is an important mechanism of apoptosis disequilibrium in cancer. Cellular inhibitors of apoptosis proteins (IAPs) represent a family of evolutionarily conserved apoptosis suppressors, which are known to be dysregulated in many cancers; that said, cancer cells might use the disequilibrium to retard apoptotic processes or stay in an apoptosis-resistant state [4, 5].
Therefore, seeking for sensitive and specific treatments that can restore the perturbation of apoptosis to a state of equilibrium in cancer cells is a challenge. Previous studies have focused on Chinese herbal medicine for its employment for centuries in the treatment of patients as well as its positive effects on tumors. Rather than focusing on the ablation of tumors per se, Chinese medicine focuses on correcting the imbalance of apoptosis. Evidence has been accumulating over decades that natural compounds of herbal medicine or formula are responsible for correcting apoptotic disequilibriums or resetting of apoptotic thresholds. A range of signaling pathways have been involved in the favorable effects of Chinese medicine in the treatment of cancers. As the domain continues to develop and novel molecular mechanisms are still being characterized, we have retrieved the latest 5 years of literature related to tumor apoptosis in response to herbal medicine. We also present literature on natural compounds from Chinese medicine with druggable potential as novel apoptosis-inducing agents.
2. Chinese herbal medicine that induces intrinsic apoptosis in human cancers
The intrinsic apoptosis pathway is driven by intercellular and extracellular perturbations such as oxidative stress, DNA damage, and chemo- and radiotherapies, which result in mitochondrial dysfunction and release of cytochrome c in the cytoplasm. Initiator caspase-9 is then activated, and executioner caspase-3 precipitates the apoptotic process. During this process, Bcl-2 family proteins which are involved in the activation of intrinsic apoptosis have been identified to play a role by either activating pro-apoptotic pathways that cause the subsequent efflux of cytochrome c or inhibit cytochrome c release. Pro-apoptotic proteins include Bax, Bid, and Bad, among others. The other subtype presenting anti-apoptotic activity contains Bcl-2 and Bcl-xL. When procaspase-9 forms, the caspase cascade will be in turn activated and caspase-2, caspase-8, caspase-9, and caspase-10 initiate the process of apoptosis, while caspase-6, caspase-7, and mainly caspase-3 precipitate the cell apoptosis. This is totally different from extrinsic apoptosis, which is mediated by death receptors. As membrane receptors such as Fas, TNF receptors will interact with corresponding ligands to recruit relevant adaptor proteins, followed by the recruitment of a series of downstream factors, in particular caspase-8, which is the critical mediator to activate the caspase cascade [6, 7] (Figure 1).
Evidence has been accumulating, across the last few decades, that dysfunctional apoptosis in cancer partly leads to the immortality property of cancer cells . With well-reported observations of good curative effects on multiple cancers as well as clinical application of centuries, attention has been extensively attracted to Chinese herbal medicine. Substantial laboratory evidence has unveiled that Chinese herbal medicine is able to recover the defective apoptosis via intrinsic apoptotic pathway, which eventually is in favor of tumor suppression (Table 1). Interestingly, Chinese herbal medicine that only involves the regulation of the extrinsic pathway has been rarely reported.
|Name of Chinese herbal medicine||Cancer type||Mechanism of action||Ref.|
|Osteosarcoma||UPR and ER stress||[8, 9]|
|Cervical cancer||ER stress|||
|Cervical cancer||ROS stress|||
|Chinese bayberry (flavonoids)||Ovarian cancer||Bcl-2 regulation|||
|Breast cancer||Bcl-2 regulation|||
|Colon cancer||Bcl-2 regulation|||
|Colon cancer||Cytochrome c release|||
|Colon cancer||ROS stress|||
|Colorectal cancer||Bax regulation|||
|Pancreatic cancer||Bcl-2 regulation|||
|Gastric cancer||Bax, Bcl-2 regulation|||
|Liver cancer||ER stress|||
|HCC||Bax, Bcl-2 regulation|||
|Melanoma||Bax, Bcl-2 regulation|||
|HCC||Cytochrome c release|||
Osteosarcoma is a type of cancer existing in a bone. Most cases occur among children and adolescents. Polyphyllin I (PPI) is extracted from
Cervical cancer is the fourth most common female malignancy in the world. Despite preventive vaccines against human papillomavirus (HPV) which are now commercially available and which have been shown to be safe and effective, there are still a large number of women, in particular in low- and middle-income countries, who are less likely to have access to HPV vaccines or screening of cervical cancer due to geographical, economic, and political barriers. Icaritin, a native compound derived from the Chinese herb
Ovarian cancer and breast cancer are malignancies that commonly occur in females. The treatment with Chinese bayberry leaf flavonoids increased the expression of cleaved caspase-3 and caspase-7, which induced intrinsic apoptosis with the activation of Erk-dependent caspase-9, as well as increased expression of the pro-apoptotic proteins Bad and Bax and decreased levels of anti-apoptotic proteins Bcl-xL and Bcl-2 . Bakuchiol is an active constituent of Chinese herb
Colon cancer is worldwide and is considered the third most commonly diagnosed cancer clinically. To identify novel specific and effective therapeutic strategies for colon cancer is extremely essential. Natural products have gained increasing attention lately. Puerarin 6″-O-xyloside (PRX), a natural compound, is derived primarily from the root of the
Colorectal cancer and colon cancer are clearly related and often used interchangeably. These two terms are often believed to be the subset of the other or even the same thing. In truth, despite similarities, there is still variation including sex predilection, anatomy, disease recurrence, surgery, and invasion of nearby tissues, not the least of which are the development ways of the two diseases.
Despite the fact that the incidence of gastric cancer has declined across the globe over the past century, there is still a startling lack of effective therapeutics.
Globally, liver cancer ranks as the sixth most common form of cancer. With the growing prevalence of liver cancer, it remains a major killer worldwide. Patients’ status is dismayingly unsatisfying unless liver cancer is caught early and specific therapeutic methods are being discovered . Celastrol is a pharmacologically active compound originally identified from the root bark of the Chinese herb “Thunder of God Vine” (
Lung cancer has been one of the leading causes of mortality in this era. With the etiologic factors of lung cancer being more complex such as environmental pollution, industrialization, and urbanization, cases of lung cancer increase across the world and account for nearly 20% of cancer-caused deaths. Studies on the new ways of diagnosis and treatment have played an important role in the tertiary prevention of lung cancer.
Leukemia is a group of life-threatening malignant disorders which often originate in the blood and bone marrow. The acute leukemia is more prevalent among adolescent and young adult population.
Total saponins isolated from
3. Both intrinsic and extrinsic apoptotic pathways involved in Chinese herbal medicine-induced apoptosis in human cancers
From a molecular standpoint, extrinsic apoptosis and intrinsic apoptosis are strikingly different. But on the whole, the two pathways are sometimes related. Receptor trimerization can lead to recruitments of several death domains and subsequent recruitment and activation of caspase-8 and caspase-10, which then either activate the intrinsic apoptotic pathway through cleavage of the BID or initiate extrinsic apoptosis directly by activating executioner caspase-3, caspase-6, and caspase-7 to induce efficient cell death (Figure 1). Previous efforts have reported that both intrinsic and extrinsic apoptoses may coexist when cancer cells were exposed to Chinese herbal medicine (Table 2).
|Name of Chinese herbal medicine (active constituent)||Cancer type||Mechanism of action||Ref.|
|Cervical cancer||IAP; Fas|||
|Cervical cancer||MMP; Fas|||
|Ovarian cancer||Bcl-2, Bcl-xL; Fas|||
|Chinese bayberry (prodelphinidins)||Ovarian cancer||Bcl-2, Bcl-xL; DR5, Fas|||
|Breast cancer||Bax, Bcl-2; Fas|||
|Prostate cancer||Bax, Bcl-2, caspase-9; caspase-8|||
|Lewis lung cancer||Bax, Bcl-2; Fas, p-p38|||
|Lung cancer||Cytochrome c; Fas|||
|Lung cancer||PUMA, Bax; DR5|||
|Lung cancer||MMP, Fas|||
|Head and neck squamous cell||Caspase-9; caspase-8|||
|Liver cancer||Caspase-9; caspase-8|||
|Mantle cell lymphoma||Caspase-9; caspase-8|||
|Oral squamous cell carcinoma||ROS; DR4|||
|Skin cancer||Sp1; Fas|||
|Glioblastoma||Bax, Bcl-2, caspase-9; caspase-8, Fas|||
|Leukemia||Bax, Bcl-2, caspase-9; caspase-8|||
Butein is a subtype of chalcones, which is widely biosynthesized in plants. Butein has been identified to be extractable from Chinese herbal medicine and possess different pharmacological activities. Recent works reported that butein owned abilities of inhibiting proliferation and inducing apoptosis both in vivo and in vitro. A finding suggested that butein could decrease cervical cancer cell viability via pro-apoptotic effect, which involved inhibition of IAP proteins and activation of both extrinsic and intrinsic pro-apoptotic pathways. Therefore, butein may be applicable for cervical cancer treatment .
Celastrol is an active ingredient derived from
4. Chinese herbal medicine that is favorable in reducing the drug resistance in human cancers
Despite significant improvements in cancer treatment and emergence of a substantial number of novel therapeutics, cure rates for most malignancies remain suboptimal. Treatment resistance is less likely predicted for individual patients and is being the largest obstacle to the success of recovery. The most targeted therapies and chemotherapeutics for cancer disrupt cancer cells via the generation of pro-death signaling molecules and subsequent initiation of programmed cell death. Based on facts mentioned previously, defects in apoptotic pathways that make tumor cells fail to die are believed to be one of the reasons for resistance acquisition. Successfully targeting apoptotic pathways with Chinese herbal medicines may shed a new light on cancer therapy (Table 3).
|Name of Chinese herbal medicine (active constituent)||Cancer type||Resistant drugs||Ref.|
|Blueberry (pterostilbene)||Oral cancer||Cisplatin|||
|Non-small cell lung cancer||TRAIL|||
|Huaier (extracts)||Hepatocellular carcinoma||Oxaliplatin|||
|Wild mushroom (clitocine)||Colon cancer||TRAIL|||
Pterostilbene is a natural polyphenolic compound chemically related to resveratrol, which has received FDA GRAS status in 2007. Pterostilbene exhibits antitumor, antioxidant, and anti-inflammatory activities and is primarily found in blueberries, almonds, grape leaves, and vines. Effects of pterostilbene on cisplatin-resistant oral cancer cells and the mode of action were explored by researchers. By using pan-caspase inhibitor and directly testing DNA breakage of human oral CAR cells, pterostilbene was found to trigger caspase-dependent apoptosis, suggesting that intrinsic apoptotic cascade was involved in the effect of pterostilbene in oral cancer . A heat-sensitive sesquiterpene named furanodiene is extractable from the essential oil of
5. Derivatives of compounds from Chinese herbal medicine that are explored for cancer treatment
Substantial native compounds are identified to possess inhibitory effects against multiple cancers. To provide therapeutic alternatives for cancer therapy and develop more efficient and specific cancer treatments, more similar compounds are being produced from naturally occurring constituents of medicinal herbs (Table 4).
|Name of Chinese herbal medicine (active constituent)||Cancer type||Derivatives||Ref.|
|Prostate, lung, cervical, ovarian, and breast cancers||Dihydroartemisinin|||
|Non-small cell lung cancer||Compound 14|||
|Genera ||Leukemia||Compound 2|||
|Esophagus cancer||Compound 19|||
|White birch (betulinic acid)||Prostate, gastric, and melanotic cancers||Compound 3k|||
The natural extract artemisinin has been gaining great attention in the medical field since Chinese scientist Tu Youyou was granted Nobel prize for his discovery of artemisinin. A study lately reported that derivatives of artemisinin have great antineoplastic activities. Researchers synthesized dihydroartemisinin (DHA) and applied it in the management of tumor cell lines including PC-3, A549, HeLa, OVCAR-3, and MCF-7. The results showed that combination of DHA and doxorubicin markedly regulated the caspase cascade through the intrinsic apoptotic pathway. DHA and doxorubicin also had a significant favorable effect in vivo. This study suggested that DHA might be a potential therapeutic agent against several types of cancer . AG36 is the biotransformation product of triterpenoid saponin from
6. Conclusions and perspectives
Dysregulation of programmed cell death acts as a natural barrier in survival and dissemination of cancer cells, whereas, malignant cells evolve many tricks to modify or generate some key modulators to evade programmed cell death. Apoptosis is one of the primary programmed cell death mechanisms, and extensive reports have identified intrinsic and extrinsic apoptosis pathways in cells. Its role in tumor proliferation is rather complex as different apoptotic pathways may cross talk or coexist in cancer. The decision taken by a cell to undergo apoptosis is regulated by various factors such as exogenous or endogenous damage.
For a long time, complementary medicine, in particular traditional Chinese medicine, has been extensively employed in practice due to good outcomes for patients in the treatment of either serious diseases or ailments. Recent attention has increasingly focused on the function of Chinese medicine on cancer and relevant molecular mechanisms. Chinese medicinal herbs may be of great value in the management of malignancies. This review retrospectively documented experimental data and precise effects of various herbs on tumor biology, especially the roles of apoptotic pathways in modulatory processes. Chinese herbal medicine serves to correct internal disequilibriums via the modulation of apoptosis and eventually contributes to cancer repression.
As the field of Chinese herbal medicine develops rapidly and apoptosis is not the only type of programmed cell death, which has expanded to include autophagy, and necrosis, among others, novel mechanisms of action that may be favorable in oncotherapy are still being characterized. We anticipate a major focus will be placed on other programmed cell death mechanisms as well as investigating potential functions of Chinese herbal medicines in such death pathways.
The study was financially supported by grants from the research council of the University of Hong Kong (Project Codes: 104004092, 104004460, 104004746), the Research Grants Committee (RGC) of Hong Kong, HKSAR (Project Codes: 764708, 766211, 17152116), Wong’s Donation on Modern Oncology of Chinese Medicine (Project code: 200006276), Gala Family Trust (Project Code: 200007008), and Innovation Technology Fund of Hong Kong (ITF. Project code: 260900263).
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