Apoptosis Genes and Resistance to Cancer Therapy: What Does the Experimental and Clinical Data Tell Us?

Abstract

The dominant paradigm in cancer treatment is that cancer cells die from the common pathway of apoptosis subsequent to DNA damage by anticancer agents and that cells resistant to apoptosis are resistant to therapy. In this review we trace the logic that brought about this view and discuss whether the clinical and experimental data that have now accumulated over the past decade support the position. We show that there is support for the apoptosis model only for certain malignancies of hematopoietic origin. For the majority of cancers (which are of epithelial origin), even though some may exhibit apoptosis after treatment, there is little or no support for the concept that apoptosis, and the genes that govern it, determine the response to therapy. In general, whether apoptosis matters for overall tumor response depends on how soon after treatment apoptosis occurs. If it occurs early (within 4 to 6 hours after treatment), it is likely to be important for determining the overall response of the cell or tumor. This is the case for some tumors of myeloid and lymphoid origin. On the other hand, if apoptosis occurs long after exposure, 24-48 hrs, and usually after mitosis, then it is unlikely to be the determinant of cytotoxicity, and modifying it is unlikely to affect overall cell killing. This is the situation for most, if not all, tumors of epithelial or mesenchymal origin. What then causes cancer cells to die following treatment with anticancer agents? The evidence from ionizing radiation is clear: DNA damage leading to chromosome breaks. We argue that the situation is similar for most anticancer drugs. Indeed inability to repair the DNA damage produced by these agents, and the levels of the proteins involved in these repair processes, may explain the treatment sensitivity of some cancers. Further clinical studies in this area are needed.

Extreme anti-oxidant protection against ionizing radiation in bdelloid rotifers

“…Effects that have been proposed in this regard include altered gene expression resulting from aberrant DNA cytosine methylation (23), centrosome amplification leading to multipolar mitosis (24), and self-sustaining production of hydrogen peroxide and elevated oxidative stress associated with mitochondrial dysfunction (25). Indeed, the question of how IR kills cells, with its important implications for radiotherapy, is a matter of continuing debate (26,27). The parallel that we find between radiosensitivity and anti-oxidant status may well extend to diverse animal species and cell types.…”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…Surprisingly, to our knowledge, these response pathways have not been investigated concurrently in a single pre-clinical or clinical study that would correlate these end points with tumor response or overall survival. It has been suggested that apoptosis is an insufficient measure of the response of tumors to therapy (Brown and Wouters, 1999;Brown and Wilson, 2003). Our current understanding points to significant cross-talk among different response pathways.…”

“…Clinical studies have not definitively indicated that apoptosis is primarily responsible for tumor responses (Brown and Wouters, 1999;Brown and Wilson, 2003). Although these clinical data are not in conflict with the recognized role that evasion of apoptosis has in tumorigenesis (Hanahan and Weinberg, 2000), some pre-clinical data challenge the proposition that apoptosis is the only mediator of treatment response (Brown and Wouters, 2001).…”

Concomitant Inhibition of MDM2 and Bcl-2 Protein Function Synergistically Induce Mitochondrial Apoptosis in AML

“…They induce p53 activation and apoptosis, 32,33 and induction of apoptosis has been shown to be a key determinant of drug response in AML. 34 Meanwhile, AraC and doxorubicin cause cell cycle arrest in S-and G 2 /M-phases, respectively. 35,36 Our findings suggest that the cell cycle arrest induced by AraC or doxorubicin would not protect leukemia cells from p53-dependent apoptosis.…”