SERCA and P-glycoprotein inhibition and ATP depletion are necessary for celastrol-induced autophagic cell death and collateral sensitivity in multidrug-resistant tumor cells

Su Wei Xu, Betty Yuen Kwan Law, Steven Li Qun Qu, Sami Hamdoun, Juan Chen, Wei Zhang, Jian Ru Guo, An Guo Wu, Simon Wing Fai Mok, David Wei Zhang, Chenglai Xia, Yoshikazu Sugimoto, Thomas Efferth, Liang Liu, Vincent Kam Wai Wong

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Multidrug resistance (MDR) represents an obstacle in anti-cancer therapy. MDR is caused by multiple mechanisms, involving ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), which reduces intracellular drug levels to sub-therapeutic concentrations. Therefore, sensitizing agents retaining effectiveness against apoptosis- or drug-resistant cancers are desired for the treatment of MDR cancers. The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump is an emerging target to overcome MDR, because of its continuous expression and because the calcium transport function is crucial to the survival of tumor cells. Previous studies showed that SERCA inhibitors exhibit anti-cancer effects in Bax-Bak-deficient, apoptosis-resistant and MDR cancers, whereas specific P-gp inhibitors reverse the MDR phenotype of cancer cells by blocking efflux of chemotherapeutic agents. Here, we unraveled SERCA and P-gp as double targets of the triterpenoid, celastrol to reverse MDR. Celastrol inhibited both SERCA and P-gp to stimulate calcium-mediated autophagy and ATP depletion, thereby induced collateral sensitivity in MDR cancer cells. In vivo studies further confirmed that celastrol suppressed tumor growth and metastasis by SERCA-mediated calcium mobilization. To the best of our knowledge, our findings demonstrate collateral sensitivity in MDR cancer cells by simultaneous inhibition of SERCA and P-gp for the first time.

Original languageEnglish
Article number104660
JournalPharmacological Research
Volume153
DOIs
Publication statusPublished - 2020 Mar

Keywords

  • Apoptosis-resistant cancer
  • Autophagic cell death
  • Celastrol
  • Collateral sensitivity
  • Multidrug resistance
  • P-gp inhibitor
  • SERCA inhibitor

ASJC Scopus subject areas

  • Pharmacology

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  • Cite this

    Xu, S. W., Law, B. Y. K., Qu, S. L. Q., Hamdoun, S., Chen, J., Zhang, W., Guo, J. R., Wu, A. G., Mok, S. W. F., Zhang, D. W., Xia, C., Sugimoto, Y., Efferth, T., Liu, L., & Wong, V. K. W. (2020). SERCA and P-glycoprotein inhibition and ATP depletion are necessary for celastrol-induced autophagic cell death and collateral sensitivity in multidrug-resistant tumor cells. Pharmacological Research, 153, [104660]. https://doi.org/10.1016/j.phrs.2020.104660