Abstract
Breast cancer is the second in mortality rate malignancy among women. Despite the many advances in breast cancer treatment, there is still a need to improve drug efficacy and reduce non-specific effects. D-alpha-tocopheryl polyethylene glycol succinate (TPGS) is frequently used in the development of drug delivery systems to improve the pharmacokinetics of anti-cancer drugs and reduce multi-drug resistance. We have previously shown that TPGS not only acts as a carrier molecule but also exerts anti-cancer effects. As part of this study, we investigated the effect of TPGS with YM155, a small molecule suppressant of Survivin, in various breast cancer cell lines representing different subtypes of the disease. We aimed to evaluate the presumed synergistic effect of the TPGS-YM155 combination and reveal its mechanism of action. Our results show that the TPGS-YM155 combination acts synergistically to reduce specifically the viability of SKBR3 cells. The combination of these agents reduced activation of the AKT pathway, decreased Survivin and Bcl-2 levels, and induced caspase-dependent and independent apoptosis via the mitochondrial pathway. Importantly, the TPGS-YM155 combination did not significantly affect the viability of MCF-10A normal immortalized cells. In conclusion, the combination of YM155 and TPGS could be a promising approach against SKBR3-type breast cancer.
Highlights
Breast cancer is the most frequently diagnosed cancer among women in Europe and the United States[1,2]
In the presence of 5 nM and 10 nM YM155 alone, the viability of SKBR3 dropped to 93% and 68% respectively, while its combination with tocopheryl polyethylene glycol succinate (TPGS) (5 μΜ) reduced cell viability to 51% and 30%, respectively
In an attempt to lower the concentration of YM155 and improve its bioavailability, synergistic approaches as well as novel drug delivery systems have been developed
Summary
Breast cancer is the most frequently diagnosed cancer among women in Europe and the United States[1,2]. Despite the many recent advances in breast cancer monotherapy, several issues remain including severe adverse effects caused by high concentrations of chemotherapeutic drugs and acquired drug resistance. Both of these issues can be overcome or minimized by using agents that act synergistically. These results suggest that the markedly improved therapeutic efficacy of this combinational approach may hold significant potential for the development of future cancer treatment protocols
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