Mitochondria as therapeutic targets for cancer chemotherapy

Abstract

Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

The cytotoxic properties and preferential toxicity to tumour cells displayed by some 2,4-bis(benzylidene)-8-methyl-8-azabicyclo[3.2.1] octan-3-ones and 3,5-bis(benzylidene)-1-methyl-4-piperidones

“…5. The mitochondrial permeability transition is a critical trigger for apoptosis [28] and has been identified as a target for cancer therapy [29][30][31]. The greater ability of 2a to induce mitochondrial swelling, therefore, may have contributed to its higher cytotoxic potency in the cancer cell lines.…”

A fate worse than death: apoptosis as an oncogenic process

“…Most stimuli, including established anti-cancer therapies such as etoposide, paclitaxel or more recently developed BH3 mimetics, initiate apoptosis through the intrinsic pathway by engaging or sensitising to MOMP 80 . Based on live-cell imaging studies, the binary all-or-nothing nature of MOMP makes it difficult to envision how intrinsic stimuli could act in any other way but to kill a cell.…”

Apoptosis‐induced inhibition of CD1d‐mediated antigen presentation: different roles for caspases and signal transduction pathways

“…17 Camptothecin induces apoptosis by activating caspases; their sequential activation cleaves various substrates required for important physiological activities inside the cell, including apoptosis. 12,18 As occurs following an elevation in ceramide, camptothecin and other topoisomerase I inhibitors have been found to regulate MAPK pathways in a time-and dose-dependent manner. 19 The blocking of p38 (but not ERK1/2) has been shown to partially inhibit camptothecin-induced apoptosis.…”

“…9 Ceramide is an important second messenger during apoptosis and induces apoptosis via both caspase-dependent and-independent pathways. [10][11][12] Strategies to promote the intracellular accumulation of ceramide may thus have therapeutic utility. Ceramide also regulates various signal transduction pathways, particularly MAPK, 13 and plays an essential regulatory role in various cellular processes such as growth, differentiation, apoptosis and immune responses.…”