ABSTRACT
Resistance to chemotherapy is a major concern and often an obstacle to successful treatment of malignancies. Chemotherapy kills cancer cells through the induction of necrosis or apoptosis. Necrosis is an adenosine triphosphate (ATP)-independent process, which involves cellular death via lysis and eventual phagocytosis aftermassive cellular insult (1). Necrosis is considered a passive catabolic process, and is characterized by early plasma membrane rupture (2). Apoptosis is an energy-dependent cellular programmed death, activated by cellular damage or physiological injury, including death receptor ligation or withdrawal of survival signals (3-5). Apoptosis involves Ca2+ influx into the cytoplasm, endonuclease activation, formation of crosslinks between proteins, microtubule disruption, changes in cell membrane lipid composition, cytoplasmic condensation, chromatin fragmentation, and nuclear compaction (6). Compared to necrotic cell death, apoptosis is induced by lower doses of cytotoxins. Apoptosis is regulated by multiple interconnected signaling pathways. These pathways regulate not only apoptosis, but also survival, proliferation, and differentiation (4). The p53 gene is important in the activation of apoptosis. In an effort to survive, cancer cells have developed mechanisms to escape apoptosis. Drug resistance can occur when cells with drug-mediated damage fail to undergo apoptosis.
