Resistance to chemotherapy is a major obstacle for the success of cancer therapy and is most commonly attributed to the inability of cancer cells to die by apoptosis, the archetypal programed cell death (PCD) response. The development of anticancer drugs that can overcome this resistance to apoptosis and induce other forms of cell death is therefore paramount for efficient cancer therapy. We report that the antidepressants maprotiline and fluoxetine induce autophagic PCD in the chemoresistant Burkitt's lymphoma (BL) cell line DG-75, which does not involve caspases, DNA fragmentation or PARP cleavage, but is associated with the development of cytoplasmic vacuoles, all consistent with an autophagic mode of PCD. Autophagic PCD was confirmed by transmission electron microscopy, upregulation of Beclin-I and the extent of PCD being reduced by the autophagic inhibitor 3-MA. In contrast, these compounds induced apoptotic PCD in the biopsy-like chemosensitive BL MUTU-I cell line. We provide evidence that the chemoresistant DG-75 cells do not express the proapoptotic Bcl-2 proteins Bax and Bak, show diminished levels of stored intracellular calcium and display shortened rod-like mitochondria, all of which are known to be associated with a defective "apoptotic" response in cancer cells. PCD in the two cell lines has different Ca(2+) responses to maprotiline and fluoxetine, which may also account for their differential PCD responses. Our study, therefore, supports a new mechanistic role for maprotiline and fluoxetine as novel proautophagic agents in the treatment of resistant BL, and thus an alternative therapeutic application for these compounds.
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