Apoptosis in cancer: from pathogenesis to treatment

Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. It is also one of the most studied topics among cell biologists. An understanding of the underlying mechanism of apoptosis is important as it plays a pivotal role in the pathogenesis of many diseases. In some, the problem is due to too much apoptosis, such as in the case of degenerative diseases while in others, too little apoptosis is the culprit. Cancer is one of the scenarios where too little apoptosis occurs, resulting in malignant cells that will not die. 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, tumour metastasis and resistance to anticancer drugs. Despite being the cause of problem, apoptosis plays an important role in the treatment of cancer as it is a popular target of many treatment strategies. The abundance of literature suggests that targeting apoptosis in cancer is feasible. However, many troubling questions arise with the use of new drugs or treatment strategies that are designed to enhance apoptosis and critical tests must be passed before they can be used safely in human subjects

gamma-secretase inhibition promotes cell death, Noxa upregulation and sensitization to BH3 mimetic ABT-737 in human breast cancer cells.

International audienceABSTRACT: INTRODUCTION: Inappropriate Notch signalling, downstream of -secretase activity, is understood to have tumor-promoting function and to be associated with poor outcome in cancer, of the breast in particular. The molecular basis of anti-tumoral effects of its inhibitors, remain however poorly characterized. Moreover, the effects of their combination with the pro-apoptototic pharmacological inhibitor of Bcl2/BclxL, ABT-737, have never been evaluated. In this study, we thus specifically addressed the biological consequences of targeting -secretase and Bcl2/BclxL, alone or simultaneously, in breast cancer cell lines as well as in a novel human breast cancer ex vivo assay. METHODS: Using in vitro 2D or 3D cultures of breast cancer cells plus a novel preclinical short term ex vivo assay that correctly maintains human mammary tissue integrity and preserves tumor microenvironment, we tested the effects of the pharmalogical -secretase inhibitor GSIXII used as a single agent or in combination with ABT-737. RESULTS: We show herein that the -secretase inhibitor GSIXII, efficiently induces apoptosis in breast cancer cell lines by a process that relies on the induction of Noxa, a pro-apoptotic Bcl2-homology 3 domain (BH3)-only protein of the Bcl-2 family that functions as an inhibitor of anti-apoptotic Mcl1. GSIXII also targets mammary cancer stem-like cells since it dramatically prevents in vitro mammosphere formation. Moreover, combining GSIXII treatment with ABT-737, a BH3-mimetic inhibitor of additional anti-apoptotic proteins such as Bcl-2 and Bcl-xL leads to both synergistic apoptotic response in breast cancer cells and to an inhibitory effect on mammosphere formation. These effects are also found when a Notch transcriptional inhibitor, SAHM1, is used. Finally, we evaluated individual human tumor responses to -secretase inhibition alone or in combination with ABT-737 in ex vivo assays. Analysis of a series of 30 consecutive tumors indicated that a majority of tumors are sensitive to apoptosis induction by GSIXII and that association of GSIXII with ABT-737 leads to an enhanced induction of apoptosis in tumor cells. CONCLUSIONS: We thus provide evidence that -secretase, and downstream Notch signalling, are relevant targets in breast cancer. GSIXII, used as single agent or in combination with clinically relevant BH3-mimetics, is a promising innovative pro-apoptotic strategy to treat mammary tumors