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Medicinal plants and phytochemicals against multidrug-resistant tumor cells expressing ABCB1, ABCG2, or ABCB5: a synopsis of 2 decades

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Abstract

Multidrug resistance is a major factor causing the failure of cancer chemotherapy. Efflux pumps of the ATP-binding cassette (ABC) transporter family expel a large array of diverse anticancer drugs out of tumor cells thereby rendering them unresponsive to drug treatment. During the past 2 decades, we focused on three ABC transporters, i.e. P-glycoprotein (MDR1/ABCB1), breast cancer resistance protein (BCRP/ABCG2), and ABCB5 with the aim to find natural products with activity against multidrug-resistant cells. We investigated more than 102 cytotoxic medicinal plants and more than 228 isolated cytotoxic phytochemicals with defined chemical structures from 16 countries in Africa, Near East, Asia, and Europe for their activity to kill multidrug-resistant cells. A synopsis of these results is given in this review article. ABCB1-, ABCG2- or ABCB5-expressing cells were moderately or strongly cross-resistant to a considerable portion of plant extracts or phytochemicals, making them less suitable for the treatment of multidrug resistant tumors. While another large portion of compounds inhibited sensitive and multidrug-resistant cells with similar efficacy, a small fraction of medicinal plants and phytochemicals (3–8%) suppressed multidrug-resistant cells with even much better efficacy as their drug-sensitive counterparts. This hypersensitivity phenomenon is termed “collateral sensitivity”. These compounds may be exquisitely suited to kill otherwise resistant and refractory tumors. Molecular modes of action of collateral sensitivity as well as possibilities for further drug development, chemical derivatization of natural lead compounds and rationale phytotherapy are discussed.

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Acknowledgement

The authors are grateful for intra- and extramural funding during the past 2 decades by the Johannes Gutenberg University, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Alexander von Humboldt Stiftung, Deutscher Akademischer Austauschdienst and private donations.

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Efferth, T., Kadioglu, O., Saeed, M.E.M. et al. Medicinal plants and phytochemicals against multidrug-resistant tumor cells expressing ABCB1, ABCG2, or ABCB5: a synopsis of 2 decades. Phytochem Rev 20, 7–53 (2021). https://doi.org/10.1007/s11101-020-09703-7

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