Many pathways and proteins control the apoptosis machinery. Examples include p53, the nuclear factor kappa B, the phosphatidylinositol 3 kinase pathway, and the ubiquitin/proteosome pathway. These can be targeted by specific modulators such as bortezomib, and mammalian target of rapamycin inhibitors such as CCI-779 and RAD 001.
Full Answer
What are some promising cancer treatment strategies targeting apoptotic inhibitors?
Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction. 1. Introduction
Why target apoptotic pathways in tumour cells?
Targeting apoptotic pathways in tumour cells is a potent anticancer strategy because dead tumour cells can contribute to clinical responses but not to tumour relapse.
Which molecules could be targeted to stimulate apoptosis in cancer?
We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction.
Which therapeutic agents target the apoptosis pathway?
Some of the approved therapeutic agents directly target the intrinsic apoptosis pathway, such as venetoclax, but most of them target the apoptosis pathways indirectly, such as inhibitors of oncogenic signalling pathways, the proteasome inhibitors or HDAC.
Which of the following methods is used by cancer cells to evade apoptosis?
In some cases, cancer cells may escape apoptosis by increasing or decreasing expression of anti- or pro-apoptotic genes, respectively. Alternatively, they may inhibit apoptosis by stabilizing or de-stabilizing anti- or pro-apoptotic proteins, respectively.
How can apoptosis be used to treat cancer?
Apoptosis in Cancer The loss of apoptotic control allows cancer cells to survive longer and gives more time for the accumulation of mutations which can increase invasiveness during tumor progression, stimulate angiogenesis, deregulate cell proliferation and interfere with differentiation [2].
Does chemotherapy inhibit apoptosis?
There is an emerging realization that cancer chemotherapeutic agents act primarily by inducing cancer cell death through the mechanisms of apoptosis.
How is apoptosis used in the cytotoxicity of cancer drugs?
Apoptosis is a common stress response Clinically useful chemotherapeutic drugs inhibit processes essential for growth or proliferation, such as blocking production of DNA, mRNA or protein, directly damaging DNA or inhibiting components required for DNA replication or chromosome separation.
How does chemotherapy work apoptosis?
Chemotherapy usually uses alkylate and anthracyclines as antimetabolic agents in clinical treatments. These chemotherapeutic drugs mainly take effect through activation of caspases and calcium-dependent nucleases to induce cancer cell apoptosis.
What is apoptosis and how does it relate to cancer?
A type of cell death in which a series of molecular steps in a cell lead to its death. This is one method the body uses to get rid of unneeded or abnormal cells. The process of apoptosis may be blocked in cancer cells. Also called programmed cell death.
Does chemotherapy activate apoptosis?
Apoptosis has been considered a major mechanism of chemotherapy-induced cell death, and pathways regulating apoptosis are the focus of many preclinical drug discovery investigations.
What encourages apoptosis?
Beta-carotene, a carotenoid in orange vegetables, induces apoptosis preferentially in various tumor cells from human prostate, colon, breast and leukemia. Many more examples of dietary substan- ces inducing apoptosis of cancer cells are available.
How do you trigger apoptosis?
In cell lines intrinsic apoptosis can be induced by stimuli including removing growth factor supplements from cell media, exposure to UV light or by exerting other stressful conditions on the cell as shown on the left of Figure 1.
Can cancer cells undergo apoptosis?
Cancer cells can ignore the signals that tell them to self destruct. So they don't undergo apoptosis when they should. Scientists call this making cells immortal.
How does apoptosis affect cancer?
Cancer is viewed as the result of a succession of genetic changes during which a normal cell is transformed into a malignant one while evasion of cell death is one of the essential changes in a cell that cause this malignant transformation. Generally, the mechanisms by which evasion of apoptosis occurs can be broadly divided into: 1) disrupted balance of pro-apoptotic and anti-apoptotic proteins, 2) reduced caspase function and 3) impaired death receptor signaling. Many proteins have been reported to exert pro- or anti apoptotic activity in the cell. The Bcl-2 family of proteins is comprised of pro-apoptotic and anti-apoptotic proteins that play a pivotal role in the regulation of apoptosis, especially via the intrinsic pathway as they reside upstream of irreversible cellular damage and act mainly at the mitochondria level. When there is disruption in the balance of anti-apoptotic and pro-apoptotic members of the Bcl-2 family, the result is dysregulated apoptosis in the affected cells. This can be due to an overexpression of one or more anti-apoptotic proteins or an under expression of one or more pro-apoptotic proteins or a combination of both. Overexpression of Bcl-xL has also been reported to confer a multi-drug resistance phenotype in tumor cells and prevents them from undergoing apoptosis.
What is the role of apoptosis in the cell cycle?
Apoptosis, also known as Type 1 Programmed Cell Death (PCD) plays a critical role for maintaining homeostatic balance between the rates of cell proliferation and cell death. Other major types of PCD that also serve to trigger cell death are type II (autophagy) and type III (necrosis). The past decade has witnessed a steady accumulation of findings suggesting that apoptosis, necrosis and autophagy are often regulated by similar pathways, engage common sub-cellular sites and organelles, and even share initiator and effector molecules. Defective or inefficient apoptosis is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. An understanding of the underlying mechanism of apoptosis is important as it plays a pivotal role in the pathogenesis of many diseases. In certain disease conditions, the problem is due to too much apoptosis, such as in the case of degenerative diseases. Whereas, there is too little apoptosis with cancer, resulting in malignant cells that are not targeted for cell death. Apoptotic cell death-based therapy has received attention for the development of anticancer drugs. The mechanism of apoptosis is complex and involves many pathways. Defects can occur at any point along these pathways, leading to malignant transformation of the affected cells, tumor metastasis and resistance to anticancer drugs. Thus, a thorough understanding of apoptotic signaling pathways and insights into apoptosis resistance mechanisms are imperative to unravel novel drug targets for effective selective therapeutic strategies. At Enzo, we offer a complete set of tools for advancing apoptosis research including antibodies, activators and inhibitors, enzyme assays, and recombinant proteins.
What is the extrinsic cell death pathway?
Activation of the extrinsic cell death pathway occurs following the binding on the cell surface of “death receptors” (DRs) to their corresponding ligands such as Fas (CD95) , TNF receptor (TNFR1) and TNFR, or TRAIL. The DRs have two distinct signaling motifs: death domains (DD) and death effector domains (DED) that allow them to interact and recruit other adaptor molecules, such as FAS-associated death domain protein (FADD) and caspase-8, which can then directly cleave and activate caspase-3 and caspase-7, leading to apoptosis. Death receptor mediated apoptosis can be inhibited by a protein called c-FLIP which bind to FADD and caspase-8, rendering them ineffective.
What is the role of caspases in apoptosis?
Caspases are a family of conserved cysteine proteases that play a central role in apoptosis as both the initiators and executioners. Activated caspases cleave many vital cellular proteins and break up the nuclear scaffold and cytoskeleton. They also activate DNAase, which further degrades nuclear DNA. The removal of apoptotic cells is the final step in the execution of apoptosis. Historically, this process has presented a significant hurdle in evaluating the amount of apoptosis, as the dying cells are rapidly cleared by phagocytes, making it very difficult to detect apoptotic cells in animal tissues. The engulfment process can be divided into the following stages: (1) sensing of the apoptotic cell, (2) recognition by the phagocyte, (3) internalization of target cell, (4) ingestion, and (5) post engulfment response of the phagocyte. Dying apoptotic cells secrete “find me” and “eat me” signals that attract and recruit phagocytes.
What is the intrinsic pathway?
The intrinsic pathway is initiated by intracellular signals that act directly on targets within the cell and are mitochondria-initiated events . Internal stimuli such as irreparable genetic damage, hypoxia, extremely high concentrations of cytosolic Ca2+ and severe oxidative stress are some triggers of the initiation of the intrinsic mitochondrial pathway. The key step in the intrinsic cell death pathway is permeabilization of the mitochondrial outer membrane and the release of pro-apoptotic molecules such as cytochrome- c into the cytoplasm. This has been identified as a ‘point of no return’ after which cells are committed to cell death. This pathway is closely regulated by a group of proteins belonging to the Bcl-2 family.
What are the therapeutic strategies for activating apoptosis in cancer cells?
Other promising therapeutic strategies for activating apoptosis in cancer cells include agents that trigger the extrinsic apoptosis pathway, those that target tumour suppressor pathways or the tumour microenvironment, and combination drug therapies.
Why is apoptosis a potent anticancer strategy?
Targeting apoptotic pathways in tumour cells is a potent anticancer strategy because dead tumour cells can contribute to clinical responses but not to tumour relapse. Some of the approved therapeutic agents directly target the intrinsic apoptosis pathway, such as venetoclax, but most of them target the apoptosis pathways indirectly, such as inhibitors of oncogenic signalling pathways, the proteasome inhibitors or HDAC. Novel agents directly targeting the apoptotic pathways are under development, some with promising potential owing to high levels of tumour selectivity.
What binds to BCL-2?
BH3 mimetics bind to anti-apoptotic BCL-2 proteins, leading to activation of BAX and BAK1. Selective inhibitors of BCL-2, BCL-X L and MCL1 have reached clinical trials. Death receptor 4 (DR4) and DR5 can be activated by agonist antibodies, soluble ligands, fusion proteins of recombinant TRAIL with IgG1 or pegylated recombinant TRAIL. The modulation of oncogenic signalling pathways induces apoptosis; thus, combinations of MEK inhibitors and the dual BCL-2–BCL-X L inhibitor navitoclax are being investigated in clinical trials. Pro-survival pathways, such as AKT and MEK, inhibit apoptosis by phosphorylation of pro-apoptotic proteins such as BAD and BIM. MDM2 inhibitors have been used to target the p53 pathway and induce apoptosis. ONC201 is an agent that binds the dopamine receptors DRD2 and DRD3 (ref. 328) as well as the mitochondrial caseinolytic protease P (ClpP), leading to activation of ATF4 (refs 329, 330) and to C/EBP homologous protein (CHOP)-dependent upregulation of DR5 and cell death 331, 332. SMAC mimetics and inhibitors of IAP proteins have transitioned to clinical trials. ER, endoplasmic reticulum. MOMP, mitochondrial outer membrane permeabilization; RTK, receptor tyrosine kinase; TK, tyrosine kinase.
What is the MCL1 inhibitor?
The rationale for the therapeutic potential of these inhibitors is that MCL1 is involved in the pathogenesis of several malignancies (frequently through amplification) and is associated with resistance to chemotherapy or dual BCL-2 and BCL-X L inhibitors 230. The small molecule AM-8621 is a novel class of spiromacrocyclic MCL1 inhibitors that binds to a groove in MCL1, thus displacing BIM and inducing apoptosis. Among 952 cell lines encompassing solid tumours and haematological malignancies, the highest level of in vitro sensitivity to AM-8621 was identified in multiple myeloma, AML, lymphoma and breast cancer cell lines 64. AMG 176, a derivative of AM-8621 with a more favourable pharmacokinetic profile, showed synergy with chemotherapy and venetoclax, thus paving the way for ongoing phase I trials of AMG 176 as a monotherapy or combined with venetoclax in patients with refractory AML, lymphoma or multiple myeloma 64 (NCT03797261 and NCT02675452). AZD5991, another macrocyclic specific MCL1 inhibitor, is being investigated in trials involving patients with advanced-stage haematological malignancies 231 (NCT03218683). The MCL1 inhibitors VU661013 and S63845 were able to synergize with venetoclax in preclinical models of haematological malignancies, including venetoclax-resistant xenograft mouse models of AML, thus supporting the potential of combinatorial strategies to circumvent venetoclax resistance that might be relevant to other anti-BCL-2 agents 232, 233, 234, 235, 236. Clinical testing of these combinations will also inform the value of sequential treatments in settings in which the temporal upregulation of these proteins determines response to treatment. BH3 profiling and evaluations of the extent of BCL-2 expression in patient-derived cells could reveal anti-apoptotic addiction to BCL-2, BCL-X L or MCL1, and help to predict responses to these apoptosis-inducing drugs 51, 172, 237, 238, 239, 240, 241, 242.
What are the mechanisms of resistance to BCL2?
Several mechanisms of resistance to therapies targeting BCL-2 proteins have been described, including modulation of their expression, mutations altering their binding site or cellular localization and modifications in mitochondrial function (through prevention of pore formation). Continued exposure of lymphoma cell lines to venetoclax led to the acquisition of mutations in BCL2 affecting the BH3-binding groove 260. This in vitro result was supported by the identification of a novel mutation resulting in the amino acid substitution Gly101Val in the BCL-2 binding groove in paired specimens collected from patients with CLL before treatment and after disease progression on venetoclax 261. This mutation was not detected in patients untreated with venetoclax or in the Catalogue of Somatic Mutations in Cancer ( COSMIC) or the Genome Aggregation ( gnomAD) databases. This mutation reduces the BCL-2 binding affinity for venetoclax ~180-fold compared with that of wild-type BCL-2, without altering the affinity for BAX and BIM, thus enabling the mutant protein to retain a pro-survival effect. In patients, this mutation can be detected with highly sensitive digital droplet PCR as early as 25 months before overt CLL clinical progression, and therefore could potentially serve as an early biomarker of progression. While Gly101Val has not been detected in other B cell malignancies, another acquired mutation in BCL2 (resulting in the amino acid substitution Phe104Ile), also interfering with venetoclax binding, was described in a patient with follicular lymphoma with secondary resistance to venetoclax 262. The crystal structures of venetoclax bound to wild-type BCL-2 and the mutants G101V and F104L have been described. In addition, venetoclax affinity can be restored by the BCL2 mutation E152A in experimental models 263. Mutations in BTG1 and homozygous CDKN2A/CDKN2B deletions have also been identified in patients with venetoclax-resistant CLL 264. Considering the growing number of patients with haematological malignancies receiving treatment with BCL-2 inhibitors, an area of active ongoing investigation is that of using combinatorial strategies to overcome resistance to these inhibitors 265.
What is the trail ligand?
TRAIL, the extracellular ligand of DR4 and DR5, is a transmembrane trimeric glycoprotein that can be cleaved by metalloproteinases and released as a soluble ligand 80, 91. TRAIL is expressed on the surface of immune cells, including NK and cytotoxic T cells, and regulates the innate immune response 281 (Fig. 1 ). TRAIL binds to decoy death receptors (DcR1, DcR2, osteoprotegerin) without intracellular caspase activation 282, 283, 284, 285, 286. Direct activation of the extrinsic pathway with agonists of DR4 and DR5 has provided a compelling rationale to induce apoptosis of cancer cells with therapeutic intent 287. Other TRAIL agonists, such as CD95 agonists were associated with severe liver toxicity in preclinical models, and clinical studies involving TNF have been hampered by the induction of inflammation; however, DR4 and DR5 agonists showed selectivity towards cancer cells without damage to non-malignant tissues in preclinical models 287. In the early 2000s, a recombinant human TRAIL-activating monoclonal antibody with activity against DR4 and DR5 (dulanermin) was tested in clinical trials 288, 289, 290, 291 (Fig. 2 ). Dulanermin was extensively investigated as both a single agent and in combination with chemotherapy or rituximab, in both patients with solid tumours and those with haematological malignancies, although clinically meaningful activity was not observed 292, 293, 294, 295. These results have been attributed to the short half-life of dulanermin (30 minutes), plus a limited capacity to induce receptor clustering, binding to decoy death receptors, lack of relevant biomarkers to inform on sensitivity, epigenetic silencing of DR4, post-translational modifications of DRs (such as O-glycosylation), or decreased expression and/or density of receptors on the cellular surface 296, 297, 298, 299, 300, 301. Intracellular levels of BCL-2 family members (such as BAX and MCL1) and other regulators of the intrinsic pathway (for example, XIAP) can also mediate resistance to TRAIL agonists in type II cells 302, 303, 304. In colon cancer cell lines, the efficiency of BID cleavage by caspase was shown to influence sensitivity to TRAIL 89. In cell lines deficient in BAX and/or BAK1 and in those overexpressing BCL-2, indirect or direct targeting of XIAP circumvented resistance to TRAIL agonists 303, 305. Furthermore, the limited activity of soluble TRAIL can also be associated with a reduced ability to induce receptor clustering, as suggested by the higher responses observed with membrane-bound or oligomerized forms of TRAIL in comparative studies 306, 307.
How do immune cells activate cell death?
Immune mechanisms can activate cell death through the extrinsic pathway, for example, through TRAIL produced by natural killer cells in response to interferons or through the blockade of cell death ligands in response to anti-PD-L1.
How does apoptosis occur?
Although understanding of the detailed signaling pathways that trigger apoptosis is incomplete, this process is controlled by a number of complex proteins, which are activated by various triggers and arranged in sequential signaling modules. Apoptosis occurs through two main pathways. The first, referred to as the extrinsic or cytoplasmic pathway, is triggered through the Fas death receptor, a member of the tumor necrosis factor (TNF) receptor superfamily. 5 The second pathway is the intrinsic or mitochondrial pathway that when stimulated leads to the release of cytochrome-c from the mitochondria and activation of the death signal. 6 Both pathways converge to a final common pathway involving the activation of a cascade of proteases called caspases that cleave regulatory and structural molecules, culminating in the death of the cell ( Figure 1 ). The pathways are linked; thus, distinction between the two pathways is simplistic. Overexpression of Bcl-2 in the intrinsic pathway may lead to the inhibition of extrinsic mediated apoptosis; 7 conversely, TNFα may increase the expression of NFκB and stimulate antiapoptotic members of the Bcl-2 family proteins.
What is the role of p53 in cancer?
Loss of p53 in many cancers leads to genomic instability, impaired cell cycle regulation, and inhibition of apoptosis. After DNA damage, p53 holds the cell at a checkpoint until the damage is repaired.
What are some examples of p53?
Examples include p53, the nuclear factor kappa B, the phosphatidylinositol 3 kinase pathway, and the ubiquitin/proteosome pathway. These can be targeted by specific modulators such as bortezomib, and mammalian target of rapamycin inhibitors such as CCI-779 and RAD 001.
What is the role of survivin in cancer?
90, 91 Survivin contains a baculovirus inhibitor of apoptosis repeat protein domain that is the active domain for inhibition of apoptosis. 92 Interestingly, survivin is expressed in embryonic tissues as well as in the majority of human cancers and some premalignant tissues, but it is not expressed in most normal adult tissues. 90 Moreover, the protein may be involved in cell resistance to chemotherapeutic agents and ionizing radiation. The selective expression of survivin as well as its important antiapoptotic function have led to further studies of this molecule as a useful diagnostic marker of cancer and a potential target for cancer treatment. 92 - 94, 93, 94 In vitro and in vivo studies have shown survivin to induce apoptosis, reduce tumor growth potential, and sensitize tumor cells to chemotherapeutic drugs . This agent is showing promising results in preclinical testing and will enter clinical testing in the near future. 90
What is ATRA therapy?
ATRA is one of the first examples of targeted therapy in human cancer. It is a liposomal form of tretinoin that is administered intravenously. In acute promyelocytic leukemia (APL), a dose of 90 mg/m 2 intravenously every other day has been given for induction, followed by maintenance with the same dose three times weekly for nine months. An intravenous dose of 120 mg/m 2 three times weekly has been administered in acquired immunodeficiency syndrome-related Kaposi sarcoma. ATRA induces differentiation in APL by modulation of the PML-RARα protein. It is also thought to induce apoptosis through the extrinsic pathway by inducing the paracrine release of membrane-associated TRAIL, which leads to apoptosis in ATRA-treated APL cells and in adjacent non-ATRA responsive and non-APL cells. 59 One of the main side effects of ATRA is the ATRA syndrome that is characterized by respiratory distress, fever, pulmonary infiltrates, and pleural effusions, and it occurs in up to 26% of patients treated with the drug alone, especially in the presence of leukocytosis of more than 10,000 cells/microliter. Treatment of APL with ATRA alone or in combination with chemotherapy yields a complete remission rate as high as 85% to 95%. 60, 61
What are the fields of research that are being translated into clinical practice?
Research in molecular and cellular biology, epidemiology, immunology, radiation physics and radiobiology, information technology, and related fields begun decades ago is being translated into clinical practice of cancer prevention, early detection, and treatment at an accelerating rate.
What is the mechanism of cell death?
Abstract. Apoptosis, or programmed cell death, is a mechanism by which cells undergo death to control cell proliferation or in response to DNA damage. The understanding of apoptosis has provided the basis for novel targeted therapies that can induce death in cancer cells or sensitize them to established cytotoxic agents and radiation therapy.
What is the apoptotic pathway?
The apoptotic pathway exists in all human cells as a heavily regulated, endogenous mechanism by which cells essentially self-destruct. This ability to undergo programmed cell death has a role in several physiological processes. Even though the expression of anti-apoptotic proteins is an important physiological safeguard that prevents cellular destruction, these proteins play a pathological role in many malignancies.
Is there a void in cancer biology?
There is a significant void in cancer biology with regard to the elucidation of the mechanisms that underlie tumor formation and progression. Recently, the existence of a hierarchy within cancer cell populations has been demonstrated experimentally for several tumor types. The identification of a tumor cell subset that is capable of self-renewal and, concurrently, generation into more differentiated progeny has engendered new perspectives toward selective targeting of tumors.
Can cancer patients relapse?
Over the past decade, improvements in cancer therapy have prolonged the lives of cancer patients significantly. Nevertheless, the development of secondary tumors often leads to disease relapse. Many cancer therapies shrink the tumor mass rapidly, which can result in remarkable but frequently transient clinical remission.
Can MDR drugs be used to treat cancer?
Although the translational power of MDR-targeted drugs is debated , several approaches are being exploited to treat cancer. In fact, inhibition of kinases by small molecules and monoclonal antibodies are novel therapeutic options for many types of malignancies [35]. Used as single agents or in combination with conventional chemotherapy, these new drugs are designed to interfere with the dysregulated cellular signals that promote proliferation and survival to block tumor growth or sensitize cancer cells to death while leaving normal cells unaffected [36].
What are the two main pathways that initiate apoptosis?
( Hassan et al., 2014 ). Apoptosis is primarily initiated through two main signaling pathways: the death receptor (extrinsic) and mitochondria mediated (intrinsic) pathways. The two apoptotic pathways are linked with each other and one pathway can influence another pathway as illustrated in Figure 1 ( Igney and Krammer, 2002; Czabotar et al., 2014 ). However, an additional apoptotic pathway with growth factor receptors may also exist, which is closely related to the phosphatidylinositol-3 kinase (PI3K)–protein kinase B (Akt)–mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) pathways ( Khan et al., 2015 ). The extrinsic apoptotic pathway is triggered by the interaction between Fas and Fas ligand or tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and DR5 through activating the ligations of cell surface death receptors of TNF receptor superfamily (such as CD95L, TRAIL and TNF-α); the receptor-ligand activates caspase-8 or caspase-10 to stimulate the transcription factor nuclear factor-B (NF-κB) and mitogen-activated protein kinases (MAPKs) in adaptive, non-apoptotic signaling pathways associated with the regulation of developmental and inflammatory processes and then further to induce apoptosis ( Sessler et al., 2013 ). In the intrinsic apoptotic pathway, apoptosis can be induced by release of cytochrome-c (Cyt-c) from the intramembrane into the cytosol for assembling of apoptosome (a caspase-activating multiprotein complex) further promoting caspase-9 activation ( Luo et al., 1998; Korsmeyer et al., 2000; Green and Kroemer, 2004 ). Apoptosis can be also regulated by B-cell-lymphoma protein 2 (Bcl-2) family ( Redza-Dutordoir and Averill-Bates, 2016 ). Both pathways can promote the initiator caspases for further activation of the effector caspases, which are the main executioner of apoptosis.
What is the role of BCL-2 in apoptosis?
The Bcl-2/Bax pathway plays a key role in intrinsic apoptotic pathway, which is dependent on the ratio of Bcl-2 and Bax in the mitochondria. Specifically, Bcl-2 protein can block the efflux of Cyt-c from cytosol to mitochondria to prevent caspase activation, then further inhibiting apoptosis. Bax protein acts as apoptosis promoter while Bcl-2 protein as apoptosis suppressor ( Gross et al., 1999 ). The Bcl-2 family consists of pro-survival members such as Bcl-2, Bcl-xL, Bcl-W, Bcl-B, MCL-1, and A1/BFL-1 and pro-apoptotic members such as Bax, BAK, and possibly BOK; all the family members share the common domains of Bcl-2 homology (BH) ( Echeverry et al., 2013 ). The Bcl-2 family controls the integrity of the mitochondrial outer membrane (MOM) to regulate the intrinsic pathway for release of apoptogenic molecules; therefore, control of the integrity of MOM mediates the response to most cytotoxic therapies ( Cory et al., 2016 ). Previous reports showed that anti-apoptotic Bcl-xL protein could induce chemoresistance and inhibition of this protein revised drug resistance in melanoma cells ( Hata et al., 2015 ). Therefore, balance of Bcl-2 family members and the ratio of Bcl-2/Bax determine whether the cell is undergoing apoptosis or is surviving. Many TCMs have been proved to generate cytotoxicity and induce apoptosis via the regulation of the balance of Bcl-2 family and/or the ratio of Bcl-2/Bax in various cancer cells. Here, we review some anticancer TCMs and derived active compounds that induce apoptosis primarily via targeting the Bcl-2/Bax pathway such as Prunella vulgaris (PV), hyperoside, Rabdosia rubescens (RR) Oridonin, Solamargine (SM), the extracts of Solanum lyratum Thunb, Huaier and its extracts, Hedyotis diffusa Willd and its extracts, Gambogic acid, and Telekin.
What is the role of PI3K/Akt/mTOR in cell cycle?
PI3K/Akt/mTOR pathway is activated by transmembrane tyrosine kinase growth factor receptors and plays the key role in cell cycle, survival, proliferation, energy metabolism, and apoptosis ( Knuefermann et al., 2003; Hassan et al., 2013 ). The pathway is closely related to other apoptotic pathways and is inhibited by the negative regulator of the pathway phosphatase and tensin homolog (PTEN) ( Lim et al., 2015 ). Furthermore, the activation of the PI3K/Akt/mTOR pathway has been implicated in the pathogenesis and chemoresistance of cancer ( Degtyarev et al., 2008; Lim et al., 2015 ). Inhibition of Akt induced cell death is also associated with autophagy ( Degtyarev et al., 2008 ). Some active compounds derived from anticancer TCMs such as Silybin (Silibinin), Matrine, MASM, WM130, and YYJ18 exert their anticancer activity by mainly inhibiting the PI3K/Akt/mTOR pathway.
What is ROS in cancer?
ROS is oxygen-derived species including superoxide, hydrogen peroxide singlet oxygen, and hydroxyl radical and plays a crucial role in cancer development and apoptosis ( Simon et al., 2000; Waris and Ahsan, 2006; Hayyan et al., 2016 ). It is well known that anticancer agents can generate ROS to mainly accumulate ROS in the mitochondria of cancer cells for activating apoptotic signaling pathways including PI3K/Akt, MAPKs, NF-κB, nuclear factor (erythroidderived2)-like 2 (Nrf2)/Kelch like-ECH-associated protein 1 (Keap1), and the tumor suppressor p53 and finally induce cancer cell damage and death ( Halliwell, 2011; Jeong and Joo, 2016; Redza-Dutordoir and Averill-Bates, 2016 ). Therefore, discovery and development of anticancer agents for overproduction of ROS in cancer cells is a good strategy in cancer therapy. Interestingly, some active compounds derived from anticancer TCMs such as curcumin and its analogues, shikonin, polysaccharides of Pleurotus abalonus, jaridonin, longikaurin A, physalin A, and physalin B, exhibit the ability to increase the level of ROS and induce apoptosis in cancer cells.
What is the signaling pathway of Janus kinase?
The signaling pathway of Janus kinase (Jak)-signal transducer and STAT3 is constitutively activated and abnormally expressed in cancer cells and plays critical roles in cell survival and apoptosis ( Huang, 2007 ). Studies have shown that p-STAT3, the activated form of STAT3, is elevated in various types of cancer, and it is a marker of poor prognosis for colorectal cancer patients ( Kusaba et al., 2006 ). STAT3 induces the downstream genes encoding for cell cycle regulators, anti-apoptotic proteins, and angiogenic factors to participate in cancer development and progression ( Al Zaid Siddiquee and Turkson, 2008 ). Therefore, Jak-STAT3 signaling pathway represents a valid target for anticancer drugs and effective block of its activation could be a promising strategy for discovery and development of novel anticancer agents in cancer therapy. Some active compounds derived from anticancer TCMs such as cucurbitacin B, DACE, artemisinin, dihydroartemisinin (DHA), BDL301, ursolic acid, and 5,7-dihydroxyflavone could suppress the proliferation and induce apoptosis primarily via effectively inhibiting Jak-STAT3 signaling pathway in cancer cells.
Is chemotherapy a good treatment for cancer?
Cancer is one of the leading causes of death in the world. Chemotherapy is one of the classic and important types of cancer treatment, particularly for later stage of cancer with metastasis. Recently, great progress has been made with more and more new therapeutic drugs including chemotherapy, targeted therapy, and immunotherapy being approved for cancer therapy due to the advances in cellular and molecular biology, immunology, and genomics leading to discovery of many novel oncogenes, tumor suppressor genes, and immunologic and therapeutic targets. However, drug-induced toxicities and resistance limit the efficacy and clinical applications of therapeutic drugs. Therefore, the discovery and development of novel anticancer agents are urgently needed to improve efficacy and reduce toxicity.
