Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside

Vela, Laura; Marzo, Isabel

doi:10.1016/j.coph.2015.05.014

Cited by 82 publications

(69 citation statements)

References 88 publications

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“…Similar to the BH3 domain in BH3-only proteins, BH3 mimetics specifically interact with anti-apoptotic BCL-2 family proteins and disrupt their ability to interact with pro-apoptotic BCL-2 proteins to induce BAX/BAK-dependent apoptosis 2,39 . Among such compounds, ABT-263 (navitoclax), a dual inhibitor of BCL-X L and BCL-2, has been shown to be significantly effective in most chronic lymphocytic leukemia (CLL) patients in clinical trials, and ABT-199 (venetoclax), a selective BCL-2 inhibitor, is also effective in patients with relapsed or refractory CLL 2,40 . The three-dimensional structures of anti-apoptotic BCL-2 proteins, such as BCL-2 and BCL-X L , share a common motif consisting of four amphipathic helices that form a hydrophobic groove serving as the binding site for pro-apoptotic BH3 domains.…”

Section: The Role Of Mcl1 and Its Targeted Therapy In Lung Cancermentioning

confidence: 99%

The anti-apoptotic protein MCL1, a novel target of lung cancer therapy

Tanaka¹

2017

J Cancer Treat & Diagnosis

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Evasion of apoptosis is one of the typical hallmarks of cancer and a major mechanism for cancer development, tumor growth, and acquisition of resistance to chemotherapy. The anti-apoptotic Bcl-2 protein family, particularly MCL1 and BCL-XL, play an important role in acquisition of apoptosis evasion. MCL1 is a highly unstable protein that is constantly degraded by the ubiquitinproteasome system. An increase in MCL1 protein has been reported in many cancers, including lung cancer, through high mRNA expression or impairment of its degradation systems. To date, much evidence has shown that MCL1 is important for cancer cell survival and drug resistance in lung cancers. In this review, we discuss the role and mechanism of high MCL1 expression in lung cancer.

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Section: The Role Of Mcl1 and Its Targeted Therapy In Lung Cancermentioning

confidence: 99%

The anti-apoptotic protein MCL1, a novel target of lung cancer therapy

Tanaka¹

2017

J Cancer Treat & Diagnosis

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“…Clinical trials with ABT-263 revealed that dose-dependent thrombocytopenia occurred in all patients [36]. Therefore, the effect of ABT-263 is limited because of its restricted safety dose [13,30]. In contrast, ABT-199 only inhibits BCL-2, but not BCL-X L , and does not reduce platelet number compared with ABT-263 [37]; however, it is possible that the efficacy of specific inhibitors of BCL-2 may be limited in lymphocyte and hematopoietic cell malignancies because of specific roles of BCL-2 in lymphoid homeostasis [38].…”

Section: Limitation Of Bh3 Mimetics In Cancer Therapymentioning

confidence: 99%

“…Other BH3 mimetics, GX15-070 (obatoclax), Bl-97C1 (sabutoclax), AT-101 (gossypol) and derivatives of AT-101 have also been clinically tested, but their efficacy was only limited. Therefore, combination therapy with another anticancer drug(s) is now undergoing clinical studies [13,30].…”

Section: Targeting Apoptosis In Cancer Chemotherapymentioning

confidence: 99%

“…Among these compounds, ABT-263 (navitoclax), an orally available derivative of ABT-737, has been shown to be significantly effective in most CLL patients in clinical trials, and , also has shown to be effective in patients with relapsed or refractory CLL [13,30]. Other BH3 mimetics, GX15-070 (obatoclax), Bl-97C1 (sabutoclax), AT-101 (gossypol) and derivatives of AT-101 have also been clinically tested, but their efficacy was only limited.…”

Section: Targeting Apoptosis In Cancer Chemotherapymentioning

confidence: 99%

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BH3 mimetics: Their action and efficacy in cancer chemotherapy

Nakajima¹,

Tanaka²

2016

Integr Cancer Sci Therap

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Evading apoptosis is a hallmark of cancer, and anti-apoptotic BCL-2 family proteins are frequently highly expressed in cancers. In cancer cells, aberrant DNA replication invokes replication-associated DNA damage signaling in cancer cells; however, DNA damage-induced apoptotic signals are masked by such apoptosis evasion systems. Therefore, it is considered that targeting of apoptosis is efficient for cancer cell-selective therapeutic methods. BCL-2 family proteins are critical regulators of mitochondrion-mediated apoptosis, and 'BH3-only' subfamily proteins induce apoptosis by binding to anti-apoptotic BCL-2 family proteins via their BH3 domain. BH3 mimetics are small molecules that mimic BH3-proteins by binding to anti-apoptotic BCL-2 family proteins. To date, more than 20 compounds have been identified, and their effects in cancer therapy have been analyzed. In this review, their efficacy in cancer chemotherapy will be discussed.

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“…Gene and protein expression of Bax in breast cancer cells increase sensitivity to apoptotic stimuli and decreases tumor enlargement while, Bcl-xL is another anti-apoptotic protein that inhibits apoptosis and stimulates the progress of breast cancer (6,7,9). In cancer cells, it has been demonstrated that the Bax/Bcl-2 ratio is diminished favoring the survival of cells, but treatment with anticancer drugs increased Bax/Bcl-2 ratio producing cell apoptosis by the intrinsic pathway (6,(10)(11)(12).Caspase activity has been related to the different pathways of apoptosis, caspase-8 and caspase-10 features of the extrinsic pathway, whereas caspase-9 of the intrinsic pathway. Caspase-8 and caspase-9 (among others) are initiators of apoptosis and their activation triggers the caspase-3 effector, therefore, their increase stimulate apoptosis (5,13,14).…”

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confidence: 99%

Apoptotic effect of noscapine in breast cancer cell lines

Quisbert-Valenzuela

Calaf

2016

International Journal of Oncology

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Abstract. Cancer is a public health problem in the world and breast cancer is the most frequently cancer in women. Approximately 15% of the breast cancers are triple-negative. Apoptosis regulates normal growth, homeostasis, development, embryogenesis and appropriate strategy to treat cancer. Bax is a protein pro-apoptotic enhancer of apoptosis in contrast to Bcl-2 with antiapoptotic properties. Initiator caspase-9 and caspase-8 are features of intrinsic and extrinsic apoptosis pathway, respectively. NF-κB is a transcription factor known to be involved in the initiation and progression of breast cancer. Noscapine, an alkaloid derived from opium is used as antitussive and showed antitumor properties that induced apoptosis in cancer cell lines. The aim of the present study was to determine the apoptotic effect of noscapine in breast cancer cell lines compared to breast normal cell line. Three cell lines were used: i) a control breast cell line MCF-10F; ii) a luminallike adenocarcinoma triple-positive breast cell line MCF-7; iii) breast cancer triple-negative cell line MDA-MB-231. Our results showed that noscapine had lower toxicity in normal cells and was an effective anticancer agent that induced apoptosis in breast cancer cells because it increases Bax gene and protein expression in three cell lines, while decreases Bcl-xL gene expression, and Bcl-2 protein expression decreased in breast cancer cell lines. Therefore, Bax/Bcl-2 ratio increased in the three cell lines. This drug increased caspase-9 gene expression in breast cancer cell lines and caspase-8 gene expression increased in MCF-10F and MDA-MB-231. Furthermore, it increased cleavage of caspase-8, suggesting that noscapineinduced apoptosis is probably due to the involvement of extrinsic and intrinsic apoptosis pathways. Antiapoptotic gene and protein expression diminished and proapoptotic gene and protein expression increased noscapine-induced expression, probably due to decrease in NF-κB gene and protein expression and also by increase of IκBα gene expression induced by this drug. IntroductionCancer is a leading cause of death in both more and less economically developed countries; the burden is expected to grow worldwide due to the growth and aging of the population and improvements in early detection and treatment (1). Cancer is a major public health problem in many parts of the world. It is currently the second leading cause of death in the United States (1,2). Breast cancer, is the most frequently occurring cancer in women and some cases show slow growth with excellent prognosis, while aggressive tumors have poor prognosis (1-3). Breast tumors have also been identified into different subtypes based on the expression of estrogen receptors (ER), progesterone receptors (PR) and Her2 oncogene. The breast tumors that do not express ER, PR or Her2 are called triple-negative breast cancers and ~15% of the breast cancers fall into this category (3,4).Apoptosis is a process of programmed cell death that occurs in response to environmental stimuli and normal gro...

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Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside

Cited by 82 publications

References 88 publications

The anti-apoptotic protein MCL1, a novel target of lung cancer therapy

The anti-apoptotic protein MCL1, a novel target of lung cancer therapy

BH3 mimetics: Their action and efficacy in cancer chemotherapy

Apoptotic effect of noscapine in breast cancer cell lines

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