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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.01159

Dual Inhibition of Pirarubicin-Induced AKT and ERK Activations by Phenformin Sensitively Suppresses Bladder Cancer Growth

Mei Peng1, Jun Deng2, Sichun Zhou2, Di Xiao2,  Jiahui Long2, Nan Zhang2, Caimei He2, Miao Mo1 and  Xiaoping Yang3*
  • 1Xiangya Hospital, Central South University, China
  • 2College of Medicine, Hunan Normal University, China
  • 3Hunan Normal University, China

Activations of Akt or ERK pathway induced by clinical drugs promote therapeutic failure due to decrease of drug response and no available strategies have been developed to solve these problems. In this study, we found that pirarubicin (THP), one important chemotherapeutic drug for treating bladder cancer intravesically, dramatically elevated both phosphorylations of Akt and Erk1/2 in addition to inducing DNA damage. MK2206 or AZD6244, representative Akt and Erk1/2 inhibitors respectively, profoundly sensitized bladder cancer cells to THP treatment. Interestingly, we found that inhibition of single arm of either Akt or Erk1/2 pathway would induce the increase of another arm, indicating the existence of the crosstalk between these two pathways. Thus, simultaneous suppression of both signals may be needed for increasing the sensitivity of THP. In other hand, we revealed that phenformin efficiently inhibited both Akt and Erk1/2 phosphorylation in a dose dependent manner. Furthermore, we demonstrated that phenformin, mimicking dual inhibitors, plays dramatically synergistic action with THP both in vitro and in vivo. Our findings suggest that combination therapy of THP with dual inhibitors may constitute a successful strategy for improving chemotherapy response.

Keywords: Akt, ERK, Pirarubicin, Phenformin, Bladder cancer

Received: 19 May 2019; Accepted: 09 Sep 2019.

Copyright: © 2019 Peng, Deng, Zhou, Xiao, Long, Zhang, He, Mo and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Xiaoping Yang, Hunan Normal University, Changsha, China,