Mitochondrion as a Novel Target of Anticancer Chemotherapy

Abstract

Mitochondrial membrane permeabilization is a critical event in the process leading to physiologic or chemotherapy-induced apoptosis (programmed cell death). This permeabilization event is, at least in part, under the control of the permeability transition pore complex (PTPC). Oncoproteins from the Bcl-2 family and tumor suppressor proteins from the Bax family interact with PTPC to inhibit or facilitate membrane permeabilization, respectively. Conventional chemotherapeutic agents elicit mitochondrial permeabilization in an indirect fashion by induction of endogenous effectors that are involved in the physiologic control of apoptosis. However, an increasing number of experimental anticancer drugs, including lonidamine, arsenite, betulinic acid, CD437, and several amphipathic cationic alpha-helical peptides, act directly on mitochondrial membranes and/or on the PTPC. Such agents may induce apoptosis in circumstances in which conventional drugs fail to act because endogenous apoptosis induction pathways, such as those involving p53, death receptors, or apical caspase activation, are disrupted. However, stabilization of the mitochondrial membrane by antiapoptotic Bcl-2-like proteins reduces the cytotoxic potential of most of these drugs. Targeting of specific PTPC components may overcome this Bcl-2-mediated apoptosis inhibition. One strategy involves cross-linking of critical redox-sensitive thiol groups within the PTPC; another involves the use of ligands to the mitochondrial benzodiazepine receptor. Thus, the design of mitochondrion-targeted cytotoxic drugs may constitute a novel strategy for overcoming apoptosis resistance.

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

“…The amplification of the apoptotic signal into a clear death signal occurs when mitochondria have a loss of membrane potential. The Bcl-2 family of proteins consists of both pro-and anti-apoptotic members that can control the loss of membrane potential (Tsujimoto, 1998;Costantini et al, 2000;Lohmann et al, 2000;Raisova et al, 2001).…”

“…The depolarization of mitochondria in response to apoptotic inducing agents, such as CD437 and 4-HPR, has been reported to be necessary for the activation of caspase-9 and caspase-3 (Marchetti et al, 1999;Mologni et al, 1999;Suzuki et al, 1999;Costantini et al, 2000;Eldadah and Faden, 2000;Tartier et al, 2000). The depolarization of the mitochondrial membrane allows for the release of the pro-apoptotic proteins cytochrome c, procaspase-9, and APAF-1.…”

Association of superoxide dismutases and NAD(P)H quinone oxidoreductases with prognosis of patients with breast carcinomas

“…Excess of oxidative stress, mediated by reactive oxygen species, may cause cellular deregulation leading to cell apoptosis, 2 proliferation or tumor promotion. 3 Alkylation and topoisomerase poisoning present the major mechanisms of action of cyclophosphamide and anthracyclines, respectively.…”

Apoptosis in health and disease and modulation of apoptosis for therapy: An overview

“…p53, ceramide, Fas/ Fas L pathway. A number of agents that induce cell death independently by acting directly on mitochondrial membranes include arsenite, lonidamine, betulinic acid, and viral protein (79). Mitochondrial DNA depleting agents such as ditercalinium inhibit respiration, electron transport and oxidative phosphorylation.…”