胡椒碱对多药耐药白血病细胞的选择性细胞毒性。

Selective Cytotoxicity of Piperine Over Multidrug Resistance Leukemic Cells.

机构信息

Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.

Institute of Nutrition Josué de Castro, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.

出版信息

Molecules. 2021 Feb 10;26(4):934. doi: 10.3390/molecules26040934.

DOI:10.3390/molecules26040934

PMID:33578817

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7916575/

Abstract

Multidrug resistance (MDR) is the main challenge in the treatment of chronic myeloid leukemia (CML), and P-glycoprotein (P-gp) overexpression is an important mechanism involved in this resistance process. However, some compounds can selectively affect MDR cells, inducing collateral sensitivity (CS), which may be dependent on P-gp. The aim of this study was to investigate the effect of piperine, a phytochemical from black pepper, on CS induction in CML MDR cells, and the mechanisms involved. The results indicate that piperine induced CS, being more cytotoxic to K562-derived MDR cells (Lucena-1 and FEPS) than to K562, the parental CML cell. CS was confirmed by analysis of cell metabolic activity and viability, cell morphology and apoptosis. P-gp was partially required for CS induction. To investigate a P-gp independent mechanism, we analyzed the possibility that poly (ADP-ribose) polymerase-1 (PARP-1) could be involved in piperine cytotoxic effects. It was previously shown that only MDR FEPS cells present a high level of 24 kDa fragment of PARP-1, which could protect these cells against cell death. In the present study, piperine was able to decrease the 24 kDa fragment of PARP-1 in MDR FEPS cells. We conclude that piperine targets selectively MDR cells, inducing CS, through a mechanism that might be dependent or not on P-gp.

摘要

多药耐药性（MDR）是治疗慢性髓性白血病（CML）的主要挑战，而过表达 P 糖蛋白（P-gp）是参与这种耐药过程的重要机制。然而，一些化合物可以选择性地影响多药耐药细胞，诱导旁系敏感性（CS），这可能依赖于 P-gp。本研究旨在探讨胡椒碱（黑胡椒中的一种植物化学物质）对 CML MDR 细胞 CS 诱导的影响及其机制。结果表明，胡椒碱诱导 CS，对 K562 衍生的 MDR 细胞（Lucena-1 和 FEPS）的细胞毒性比 K562 即亲本 CML 细胞更强。CS 通过细胞代谢活性和活力、细胞形态和凋亡分析得到证实。CS 的诱导部分需要 P-gp。为了研究一种不依赖 P-gp 的机制，我们分析了多聚（ADP-核糖）聚合酶-1（PARP-1）可能参与胡椒碱细胞毒性作用的可能性。先前的研究表明，只有 MDR FEPS 细胞存在高水平的 24 kDa PARP-1 片段，这可以保护这些细胞免受细胞死亡。在本研究中，胡椒碱能够降低 MDR FEPS 细胞中的 24 kDa PARP-1 片段。我们得出结论，胡椒碱通过一种可能依赖或不依赖 P-gp 的机制，选择性地靶向 MDR 细胞，诱导 CS。