Abstract
Sepantronium bromide (YM155), originally developed against the anti-apoptotic protein survivin, performed exceptionally well in pre-clinical and phase I clinical trials. However, in phase II trials of several cancer types including breast cancer it performed poorly. Additionally, no definitive correlation between survivin level and response to therapy was found. In an attempt to understand the true reason of the late-stage failure of this promising drug, we developed YM155-resistant MCF-7 breast cancer cell line and characterized side-by-side with the drug-naïve parental cell line. Chronic YM155 treatment resulted in downregulation of survivin expression yet triggered cellular responses typical of adaptation to persistent DNA damage. Lowering endogenous antioxidant glutathione level and activity of cell cycle check-point kinase restored YM155 activity. Thus, contrary to its development as a survivin suppressant, YM155 primarily acts as a chemotherapeutic drug causing oxidative stress-mediated DNA damage. Adaptation to long-term exposure to YM155 can be prevented and/or overcome by interfering with detoxification and DNA damage-response pathways. Finally, proteins associated with DNA damage-response pathway will be more appropriate as predictive biomarkers of YM155 in breast tumor cells.
Highlights
The major function of the IAP family proteins is suppression of caspases, the effector enzymes for apoptosis [1]
Low density plating following 72 h YM155 treatment resulted in greater number of drug-tolerant colonies over a 10-day period from the YMR cells compared to its MCF-7 P counterpart (Figure 1B)
Our model of adaptive resistance was generated by exposing MCF-7, an estrogen receptor (ER)+ breast cancer (BC) cell line to escalating doses of YM155
Summary
The major function of the IAP family proteins is suppression of caspases, the effector enzymes for apoptosis [1]. In most trials, including one with HER2-negative BC patients, YM155 failed to demonstrate significant antitumor efficacy either as a monotherapy or in combination www.oncotarget.com with standard chemotherapy [9,10,11,12,13] This could partly be explained on the basis of absence of biomarker-based patient selection strategy which demands knowledge of exact mechanism of drug action. For YM155, this is true, since apart from being a survivin suppressant, it has been reported to either inhibit several proteins having anti-apoptotic and growth stimulatory functions [14, 15] or act as a potent DNA-damaging agent [16] It is unclear whether downregulation of target protein/s or execution of genotoxicity is necessary and sufficient for its anti-tumor action
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