| Summary: | Anticancer drugs induce apoptotic and non-apoptotic cell death in various cancer types. The signaling pathways for anticancer drug-induced apoptotic cell death have been shown to differ between drug-sensitive and drug-resistant cells. In atypical multidrug-resistant leukemia cells, the <i>c-Jun</i>/activator protein 1 (AP-1)/<i>p53</i> signaling pathway leading to apoptotic death is altered. Cancer cells treated with anticancer drugs undergo <i>c-Jun</i>/AP-1–mediated apoptotic death and are involved in <i>c-Jun</i> N-terminal kinase activation and growth arrest- and DNA damage-inducible gene 153 (<i>Gadd153</i>)/CCAAT/enhancer-binding protein homologous protein pathway induction, regardless of the <i>p53</i> genotype. <i>Gadd153</i> induction is associated with mitochondrial membrane permeabilization after anticancer drug treatment and involves a coupled endoplasmic reticulum stress response. The induction of apoptosis by anticancer drugs is mediated by the intrinsic pathway (cytochrome c, Cyt c) and subsequent activation of the caspase cascade via proapoptotic genes (e.g., <i>Bax</i> and <i>Bcl-xS</i>) and their interactions. Anticancer drug-induced apoptosis involves caspase-dependent and caspase-independent pathways and occurs via intrinsic and extrinsic pathways. The targeting of antiapoptotic genes such as <i>Bcl-2</i> enhances anticancer drug efficacy. The modulation of apoptotic signaling by <i>Bcl-xS</i> transduction increases the sensitivity of multidrug resistance-related protein-overexpressing epidermoid carcinoma cells to anticancer drugs. The significance of autophagy in cancer therapy remains to be elucidated. In this review, we summarize current knowledge of cancer cell death-related signaling pathways and their alterations during anticancer drug treatment and discuss potential strategies to enhance treatment efficacy.
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