Gamal-Eldeen Amira M, Alrehaili Amani A, Alharthi Afaf, Raafat Bassem M
Clinical Laboratory Sciences Department, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia.
Radiological Sciences Department, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia.
Front Pharmacol. 2022 Mar 24;13:860898. doi: 10.3389/fphar.2022.860898. eCollection 2022.
Perftoran (perfluorodecalin) is an oxygen carrier, and carboplatin is a common chemotherapy drug used worldwide for lung cancer treatment. Hypoxia is one of the factors that induce resistance of lung cancer cells to carboplatin. This study explored the role of Perftoran, as an oxygen carrier, in lowering the resistance of lung cancer cells to carboplatin through suppression of hypoxia pathway mediators. The effect of Perftoran on the resistance of human lung cancer A549 cells to carboplatin was investigated through the evaluation of cytotoxicity by MTT, cell death mode by dual DNA staining, DNA damage by comet assay, DNA platination (DNA/carboplatin adducts) by atomic absorption spectroscopy, hypoxia degree by pimonidazole, HIF-1α/HIF-2α concentrations by ELISA, expression of miRNAs (hypoxamiRs miR-210, miR-21, and miR-181a) by qRT-PCR, and the content of drug resistance transporter MRP-2 by immunocytochemical staining. Results indicated that compared to carboplatin, Perftoran/carboplatin decreased cell resistance to carboplatin by potentiating its cytotoxicity using only 45% of carboplatin IC and inducing apoptosis. Perftoran induced DNA platination and DNA damage index in cells compared to carboplatin alone. Moreover, compared to treatment with carboplatin alone, co-treatment of cells with Perftoran and carboplatin inhibited cellular pimonidazole hypoxia adducts, diminished HIF-1α/HIF-2α concentrations, suppressed hypoxamiR expression, and decreased MRP-2. In conclusion, Perftoran inhibited resistance of lung cancer cells to carboplatin through the inhibition of both hypoxia pathway mediators and the drug resistance transporter MRP-2 and through the induction of DNA/carboplatin adduct formation.
全氟萘烷是一种氧载体，而卡铂是一种在全球范围内用于肺癌治疗的常见化疗药物。缺氧是诱导肺癌细胞对卡铂产生耐药性的因素之一。本研究探讨了作为氧载体的全氟萘烷通过抑制缺氧途径介质来降低肺癌细胞对卡铂耐药性的作用。通过MTT法评估细胞毒性、通过双重DNA染色评估细胞死亡模式、通过彗星试验评估DNA损伤、通过原子吸收光谱法评估DNA铂化（DNA/卡铂加合物）、通过匹莫硝唑评估缺氧程度、通过ELISA评估HIF-1α/HIF-2α浓度、通过qRT-PCR评估miRNA（缺氧相关miR-210、miR-21和miR-181a）的表达以及通过免疫细胞化学染色评估耐药转运蛋白MRP-2的含量，研究了全氟萘烷对人肺癌A549细胞对卡铂耐药性的影响。结果表明，与卡铂相比，全氟萘烷/卡铂通过仅使用45%的卡铂IC增强其细胞毒性并诱导凋亡，从而降低细胞对卡铂的耐药性。与单独使用卡铂相比，全氟萘烷诱导细胞中的DNA铂化和DNA损伤指数。此外，与单独使用卡铂治疗相比，全氟萘烷和卡铂联合处理细胞可抑制细胞匹莫硝唑缺氧加合物、降低HIF-1α/HIF-2α浓度、抑制缺氧相关miR表达并降低MRP-2。总之，全氟萘烷通过抑制缺氧途径介质和耐药转运蛋白MRP-2以及诱导DNA/卡铂加合物形成来抑制肺癌细胞对卡铂的耐药性。
