To Kenneth K W, Poon Daniel C, Wei Yuming, Wang Fang, Lin Ge, Fu Liwu
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
Br J Pharmacol. 2015 Aug;172(16):4089-106. doi: 10.1111/bph.13189. Epub 2015 Jun 26.
Pelitinib is a potent irreversible EGFR TK inhibitor currently in clinical trials for the treatment of lung cancer. Hyperthermia has been applied concomitantly with chemotherapy and radiotherapy to enhance treatment outcome. In this study, we investigated the ability of the combination of pelitinib with other conventional anticancer drugs to specifically target cancer cells with up-regulated efflux transporters ABCB1/ABCG2 after hyperthermia as a novel way to eradicate the cancer stem-like cells responsible for cancer recurrence.
Alterations in intracellular topotecan accumulation, the efflux of fluorescent probe substrates, expression and ATPase activity of ABCB1/ABCG2 and tumoursphere formation capacity of side population (SP) cells sorted after hyperthermia were examined to elucidate the mechanism of pelitinib-induced chemosensitization.
While pelitinib did not modulate ABCB1/ABCG2 expressions, the combination of pelitinib with transporter substrate anticancer drugs induced more marked apoptosis, specifically in cells exposed to hyperthermia. The flow cytometric assay showed that both ABCB1- and ABCG2-mediated drug effluxes were significantly inhibited by pelitinib in a concentration-dependent manner. The inhibition kinetics suggested that pelitinib is a competitive inhibitor of ABCB1/ABCG2, which is consistent with its ability to stimulate their ATPase activity. SP cells sorted after hyperthermia were found to be more resistant to anticancer drugs, presumably due to the up-regulation of ABCB1 and ABCG2. Importantly, pelitinib specifically enhanced the chemosensitivity but reduced the tumoursphere formation capacity of these SP cells.
This study demonstrated a novel approach, exploiting drug resistance, to selectively kill cancer stem-like cells after hyperthermia.
培利替尼是一种强效不可逆的表皮生长因子受体酪氨酸激酶（EGFR TK）抑制剂，目前正处于治疗肺癌的临床试验阶段。热疗已与化疗和放疗联合应用以提高治疗效果。在本研究中，我们探究了培利替尼与其他传统抗癌药物联合使用，在热疗后特异性靶向具有上调的外排转运蛋白ABCB1/ABCG2的癌细胞的能力，以此作为根除导致癌症复发的癌症干细胞样细胞的新方法。
检测热疗后分选的侧群（SP）细胞中拓扑替康细胞内蓄积的变化、荧光探针底物的外排、ABCB1/ABCG2的表达及ATP酶活性以及肿瘤球形成能力，以阐明培利替尼诱导化学增敏的机制。
虽然培利替尼不调节ABCB1/ABCG2的表达，但培利替尼与转运蛋白底物抗癌药物联合使用可诱导更明显的细胞凋亡，特别是在接受热疗的细胞中。流式细胞术检测表明，培利替尼以浓度依赖的方式显著抑制ABCB1和ABCG2介导的药物外排。抑制动力学表明培利替尼是ABCB1/ABCG2的竞争性抑制剂，这与其刺激它们的ATP酶活性的能力一致。热疗后分选的SP细胞对抗癌药物更具抗性，可能是由于ABCB1和ABCG2的上调。重要的是，培利替尼特异性增强了这些SP细胞的化学敏感性，但降低了其肿瘤球形成能力。
本研究证明了一种利用耐药性在热疗后选择性杀死癌症干细胞样细胞的新方法。
