Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies

Abstract

Apoptosis is a form of programmed cell death that results in the orderly and efficient removal of damaged cells, such as those resulting from DNA damage or during development. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Deregulation in apoptotic cell death machinery is an hallmark of cancer. Apoptosis alteration is responsible not only for tumor development and progression but also for tumor resistance to therapies. Most anticancer drugs currently used in clinical oncology exploit the intact apoptotic signaling pathways to trigger cancer cell death. Thus, defects in the death pathways may result in drug resistance so limiting the efficacy of therapies. Therefore, a better understanding of the apoptotic cell death signaling pathways may improve the efficacy of cancer therapy and bypass resistance. This review will highlight the role of the fundamental regulators of apoptosis and how their deregulation, including activation of anti-apoptotic factors (i.e., Bcl-2, Bcl-xL, etc) or inactivation of pro-apoptotic factors (i.e., p53 pathway) ends up in cancer cell resistance to therapies. In addition, therapeutic strategies aimed at modulating apoptotic activity are briefly discussed.

Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) enhances IL-10 production through the activation of Bruton's tyrosine kinase and STAT3

“…Pharmacological therapies to treat tumors typically induce the death of cells that are rapidly proliferating or by blocking signal transduction pathways that directly increase tumor cell survival (Dominguez-Brauer et al, 2015; Pistritto et al, 2016). However, an alternative approach may be to block the production of pro-survival factors, such as IL-10.…”

Inhibitory effects of lapachol on rat C6 glioma in vitro and in vivo by targeting DNA topoisomerase I and topoisomerase II

“…Most current chemotherapeutic agents act through the activation of the apoptosis signal pathway [20]. Our hoechst 33258 staining and Annexin V-FITC/PI staining results indicated that lapachol could significantly induce the apoptosis of C6 cells in dose dependent manners (Fig.…”

Molecular mechanisms of neoplasia

“…Jest to możliwe dzięki wydzielaniu proapo-effectiveness of current therapies. This is possible due to the extrinsic induction of apoptosis by TRAIL signalling or inhibition of the antiapoptotic activity of Bcl-2 protein or IAP protein [43,44].…”

“…Szczegółowe poznanie ścieżek apoptotycznych i antyapoptotycznych oraz zrozumienie funkcji białek regulatorowych zaangażowanych w te szlaki pozwala na uwrażliwienie komórek nowotworowych na apoptozę, a tym samym poprawę skuteczności obecnych terapii. Możliwe jest to dzięki zewnątrzpochodnemu wywoła-niu apoptozy poprzez sygnalizację TRAIL lub zahamowanie antyapoptotycznej aktywności białka Bcl-2 lub białka IAP [43,44].…”