Mirzaei Seyed Abbas, Gholamian Dehkordi Neda, Ghamghami Mahsa, Amiri Amir Hossein, Dalir Abdolahinia Elaheh, Elahian Fatemeh
Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran.
Department of Pharmaceutical Biotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Iran.
Toxicol Appl Pharmacol. 2017 Dec 15;337:22-29. doi: 10.1016/j.taap.2017.10.018. Epub 2017 Oct 25.
Furanocoumarins derived from herbal and citrus extracts can act as antibacterial, antioxidant, immunomodulator, apoptotic, and selective anticancer agents, prompting a biological investigation to determine and predict their clinical therapeutic significance. Here, the cell cytotoxic effects of bergapten and xanthotoxin were analyzed alone and in combination with standard chemotherapeutics on three multidrug resistant cells and their nonresistant parental counterparts. The furanocoumarins modulatory effects on MDR1, BCRP, and MRP pump expression and function were investigated. Although quantitative real time PCR demonstrated that the MDR transcript level changes in a time dependent manner, flow cytometric analyses using fluorescent-labeled antibodies have indicated that bergapten and xanthotoxin had no significant effect on the protein levels. FACS analyses indicated that these prominent anticancer agents significantly blocked MDR1, BCRP, and MRP transporter function. Maximum furanocoumarin-mediated pump activity blockage in the MDR-resistant cells was quantified as 87% of normal and consequently, chemotherapeutic accumulation increased up to 2.7-fold and cytotoxicity tension increased 104-fold. MDR1 efflux kinetics also revealed that the maximum velocity and the pump affinity to daunorubicin were uncompetitively decreased. We conclude that bergapten and xanthotoxin are cytotoxic agents capable of preventing daunorubicin, mitoxantrone, and cisplatin binding to ABC-transporters and subsequently inhibiting their efflux out of cells and they may be a potential combination therapy for malignant cancers.
源自草药和柑橘提取物的呋喃香豆素可作为抗菌、抗氧化、免疫调节、诱导凋亡和选择性抗癌剂，促使人们开展生物学研究以确定和预测它们的临床治疗意义。在此，单独分析了补骨脂素和花椒毒素对三种多药耐药细胞及其非耐药亲本细胞的细胞毒性作用，并将其与标准化疗药物联合进行了分析。研究了呋喃香豆素对MDR1、BCRP和MRP转运蛋白表达及功能的调节作用。尽管定量实时PCR表明MDR转录水平呈时间依赖性变化，但使用荧光标记抗体的流式细胞术分析表明补骨脂素和花椒毒素对蛋白水平无显著影响。FACS分析表明，这些显著的抗癌剂显著阻断了MDR1、BCRP和MRP转运蛋白的功能。在MDR耐药细胞中，呋喃香豆素介导的转运蛋白活性最大阻断量被量化为正常水平的87%，因此，化疗药物的蓄积增加了2.7倍，细胞毒性张力增加了104倍。MDR1外排动力学还显示，柔红霉素的最大速度和转运蛋白亲和力呈非竞争性降低。我们得出结论，补骨脂素和花椒毒素是细胞毒性剂，能够阻止柔红霉素、米托蒽醌和顺铂与ABC转运蛋白结合，随后抑制它们从细胞中流出，它们可能是恶性癌症的一种潜在联合治疗方法。
