Phosphatidylserine-targeting bis(zinc-dipicolylamine) farnesol inhibits ATP production in cancer cells to overcome multidrug resistance

Wei Huang; Xuan Nie; Xiao-Hong Zhou; Lei Qiao; Hong-Jie Gao; Jing Zang; Long-Kang Yu; Long-Hai Wang; Ye-Zi You

Supramolecular Materials (Dec 2024)

Phosphatidylserine-targeting bis(zinc-dipicolylamine) farnesol inhibits ATP production in cancer cells to overcome multidrug resistance

Wei Huang,
Xuan Nie,
Xiao-Hong Zhou,
Lei Qiao,
Hong-Jie Gao,
Jing Zang,
Long-Kang Yu,
Long-Hai Wang,
Ye-Zi You

Affiliations

Wei Huang: Key Laboratory of Precision and Intelligent Chemistry, University of Science and Technology of China, Hefei, Anhui, China; Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui, China; Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Anhui Provincial Key Laboratory of Precision Pharmaceutical Preparations and Clinical Pharmacy, Hefei, Anhui, China
Xuan Nie: Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Anhui Provincial Key Laboratory of Precision Pharmaceutical Preparations and Clinical Pharmacy, Hefei, Anhui, China
Xiao-Hong Zhou: Key Laboratory of Precision and Intelligent Chemistry, University of Science and Technology of China, Hefei, Anhui, China; Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui, China
Lei Qiao: Key Laboratory of Precision and Intelligent Chemistry, University of Science and Technology of China, Hefei, Anhui, China; Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui, China
Hong-Jie Gao: Key Laboratory of Precision and Intelligent Chemistry, University of Science and Technology of China, Hefei, Anhui, China; Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui, China
Jing Zang: Key Laboratory of Precision and Intelligent Chemistry, University of Science and Technology of China, Hefei, Anhui, China; Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui, China
Long-Kang Yu: Key Laboratory of Precision and Intelligent Chemistry, University of Science and Technology of China, Hefei, Anhui, China; Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui, China
Long-Hai Wang: Key Laboratory of Precision and Intelligent Chemistry, University of Science and Technology of China, Hefei, Anhui, China; Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui, China; Corresponding author.
Ye-Zi You: Key Laboratory of Precision and Intelligent Chemistry, University of Science and Technology of China, Hefei, Anhui, China; Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui, China; Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Anhui Provincial Key Laboratory of Precision Pharmaceutical Preparations and Clinical Pharmacy, Hefei, Anhui, China

Journal volume & issue: Vol. 3
p. 100068

Abstract

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Multidrug resistance significantly impedes the efficacy of cancer chemotherapy. Resistance often arises from the reduced cellular uptake of chemotherapeutic drugs, a process crucial for their cytotoxic effects. This reduction is frequently due to transmembrane efflux pumps powered by ATP from mitochondria and the cytoplasmic matrix, leading to lower intracellular concentrations of these drugs. This study introduces an amphiphilic molecule, bis(zinc-dipicolylamine) farnesol (Bis-ZnDPA), which targets phosphatidylserine (PS) – a negatively charged phospholipid prominently displayed on the outer leaflet of cancer cell plasma membranes. Integrating the hydrophobic segment of Bis-ZnDPA into the plasma membrane disrupts its integrity, potentially leading to hole formation and facilitating the uptake of chemotherapeutic drugs. Furthermore, the binding of Bis-ZnDPA to phosphatidylserine inhibits ATP production caused by Ca2+ influx and deregulation of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, reducing the efflux of drugs from cells. The results indicate the potent synergistic effect of Bis-ZnDPA with chemotherapeutic agents, suggesting that targeting PS is a viable strategy for overcoming multidrug resistance in cancer chemotherapy.

Published in Supramolecular Materials

ISSN: 2667-2405 (Online)
Publisher: KeAi Communications Co., Ltd.
Country of publisher: China
LCC subjects: Science: Chemistry
Website: https://www.keaipublishing.com/en/journals/supramolecular-materials/

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