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Pomiferin targets SERCA, mTOR, and P-gp to induce autophagic cell death in apoptosis-resistant cancer cells, and reverses the MDR phenotype in cisplatin-resistant tumors in vivo
Qu, Yuan-Qing Song, Lin-Lin Xu, Su-Wei Yu, Margaret Sum Yee Kadioglu, Onat Michelangeli, Francesco Law, Betty Yuen Kwan Efferth, Thomas Lam, Christopher Wai-Kei Wong, Vincent Kam Wai
Qu, Yuan-Qing
Song, Lin-Lin
Xu, Su-Wei
Yu, Margaret Sum Yee
Kadioglu, Onat
Michelangeli, Francesco
Law, Betty Yuen Kwan
Efferth, Thomas
Lam, Christopher Wai-Kei
Wong, Vincent Kam Wai
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2023-04-13
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Abstract
Drug resistance in cancer has been classified as innate resistance or acquired resistance, which were characterized by apoptotic defects and ABC transporters overexpression respectively. Therefore, to preclude or reverse these resistance mechanisms could be a promising strategy to improve chemotherapeutic outcomes. In this study, a natural product from Osage Orange, pomiferin, was identified as a novel autophagy activator that circumvents innate resistance by triggering autophagic cell death via SERCA inhibition and activation of the CaMKKβ-AMPK-mTOR signaling cascade. In addition, pomiferin also directly inhibited the P-gp (MDR1/ABCB1) efflux and reversed acquired resistance by potentiating the accumulation and efficacy of the chemotherapeutic agent, cisplatin. In vivo study demonstrated that pomiferin triggered calcium-mediated tumor suppression and exhibited an anti-metastatic effect in the LLC-1 lung cancer-bearing mouse model. Moreover, as an adjuvant, pomiferin potentiated the anti-tumor effect of the chemotherapeutic agent, cisplatin, in RM-1 drug-resistant prostate cancer-bearing mouse model by specially attenuating ABCB1-mediated drug efflux, but not ABCC5, thereby promoting the accumulation of cisplatin in tumors. Collectively, pomiferin may serve as a novel effective agent for circumventing drug resistance in clinical applications. [Abstract copyright: Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.]
Citation
Qu, Y-Q., Song, L-L., Xu, S-W., Yu, M. S. Y., Kadioglu, O., Michelangeli, F., Law, B. Y. K., Efferth, T., Lam, C. W-K., & Wong, V. K. W. (2023). Pomiferin targets SERCA, mTOR, and P-gp to induce autophagic cell death in apoptosis-resistant cancer cells, and reverses the MDR phenotype in cisplatin-resistant tumors in vivo. Pharmacological Research, 191, article-number 106769. https://doi.org/10.1016/j.phrs.2023.106769
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Elsevier
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Pharmacological Research
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1043-6618