Chapters authored
Insights into the Role of Defective Apoptosis in Cancer Pathogenesis and Therapy
One form of programmed cell death (PCD) is apoptosis. Defective apoptosis is an indispensable causative factor in the development of cancer that allows cancer cells to survive longer and favors the accumulation of oncogenic mutations. Further, upregulation of antiapoptotic proteins (e.g., Bcl-2, Mcl-1) and loss of pro-apoptotic proteins (e.g., Bid, Bad, Bax, Bak) strongly favors apoptosis evasion. The ability of cancer cells to evade apoptosis is critical for the progression and clonal expansion of malignantly transformed cells. Defective apoptosis imparts proliferative advantage to cancer cells or cells with the potential to become cancerous. The mechanisms employed by cancer cells to evade apoptosis can be used in the strategic design of therapeutic regimens aimed at exploiting apoptotic signaling networks to ensure tumor-specific cell death. Therefore, to ensure tumor-specific cell death, we may need to exploit the expression and/or function of different components of apoptotic signaling that are critical for maintaining cell survival and are regulated differently in tumor cells than normal cells. Both inhibitors of anti-apoptotic proteins and activators of pro-apoptotic proteins can be used for cancer therapy. In this chapter, we attempted to summarize the knowledge about the molecular mechanisms of defective apoptosis that could be translated into the development of novel therapeutic agents and therapeutic modalities for cancer treatment.
Part of the book: Regulation and Dysfunction of Apoptosis
Targeting Oncogene Addiction for Cancer Therapy
Oncogene addiction, a term first coined by Bernard Weinstein in 2000, refers to a condition where a tumor cell, despite harboring a multitude of genetic alterations, depends on a single oncogenic pathway or oncoprotein for sustained proliferation and survival. Several lines of evidence from mammalian cell culture models, genetically modified mice models, and human intervention trials of targeted drugs have revealed that many tumors, if not all, rely on oncogene addiction for sustained proliferation and survival. Oncogene addiction strongly impacts the therapeutic response of tumors to acute oncoprotein inhibition. An important implication of oncogene addiction is that inhibiting this critical pathway, on which cancer cells become dependent, can cause selective and specific cell death in cancer cells while sparing normal surrounding cells that are not oncogene addicted. However, the mechanism by which cancer cells become dependent on a single pathway or activated oncoprotein is not precisely understood in most cases. Thus, a better understanding of oncogene addiction may provide a rationale for improving current cancer therapies and help develop novel therapeutic strategies for the management of cancer.
Part of the book: Molecular Mechanisms in Cancer