Short-term starvation (STS) has been shown to be effective in both protection of normal cell and tissues and the sensitization of a variety of tumors during chemotherapy treatment. This condition of protection/sensitization of different cell types under the same condition has been named differential stress resistance (DSR). Although the effects of fasting have been mainly attributed to reduced glucose and circulating IGF1 levels, the involvement of signaling genes regulated by glucose and growth factors in these effects of fasting remain poorly understood.
In this study we have administered the mTor inhibitor rapamycin in combination with STS and with the chemotherapy drug doxorubicin to shed light on the role of mTOR in the STS response and on its role in mediating DSR.
In a mouse allograft model for breast cancer (4T1) we show that STS and rapamycin have an additive effect in reducing tumor progression, which confirms the possibility that STS-mediated effects on cancer cells are not due to the up-regulation of mTOR. Surprisingly, we observed that the administration of rapamycin during chemotherapy sensitizes the mice to the drug leading to an increased mortality. However, this sensitizing effect could be reversed by STS.
In summary, the combination of mTor inhibition by rapamycin and STS have additive effects in retarding breast cancer tumor growth and also prevent the chemotherapy-dependent sensitization of normal cells caused by rapamycin alone. Because rapamycin is used for the treatment of certain tumors in humans, these results may have important implications for the safety of therapies using a combination of rapamycin and chemotherapy and indicate that the combination of Tor inhibitors and STS should be tested clinically.
Citation Format: Stefano Di Biase, Sebastian Brandorst, Min Wei, Valter Longo. Effects of rapamycin and fasting-cycles therapy on differential stress resistance and sensitization in breast cancer mouse models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-78. doi:10.1158/1538-7445.AM2014-LB-78