The therapeutic goal of
cancer treatment has been to trigger
tumor-selective cell death. Although cell death can be achieved not only by apoptosis (type I programmed cell death) but also by
necrosis, mitotic catastrophe, and autophagy, drugs inducing apoptosis remain the main chemotherapeutic agents in medical oncology. However,
cancer cells in their relentless drive to survive, hijack cell processes, resulting in apoptosis resistance, which underlies not only
tumorigenesis but also the inherent resistance of certain
cancers to
radiotherapy and
chemotherapy. Unlike apoptosis, which is a
caspase-dependent process characterized by nuclear condensation and fragmentation, autophagic cell death is a
caspase-independent process characterized by the accumulation of autophagic vacuoles in the cytoplasm accompanied by extensive degradation of the Golgi apparatus, the polyribosomes, and the endoplasmic reticulum, which precedes the destruction of the nucleus. The most striking evidence for proautophagic
chemotherapy to overcome apoptosis resistance in
cancer cells comes from the use of
temozolomide, a proautophagic cytotoxic drug, which has demonstrated real therapeutic benefits in
glioblastoma patients and is in clinical trials for several types of apoptosis-resistant
cancers. A number of potential common targets in autophagy and apoptosis resistance pathways, that is,
mammalian target of rapamycin (mTOR),
phosphatidylinositol 3' kinase (PI3K), and Akt have been identified. Thus, further success in certain devastating
cancers might be achieved by the combination of proautophagic drugs such as
temozolomide with mTOR, PI3K, or Akt inhibitors, or with endoplasmic reticulum stress inhibitors as adjuvant
chemotherapies.