Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
Chem Biol Interact. 2014 Jun 25;217:28-40. doi: 10.1016/j.cbi.2014.04.007. Epub 2014 Apr 18.
Tyrosine kinases play a pivotal role in oncogenesis. Although tyrosine kinase inhibitors as sunitinib malate are used in cancer therapy, emerging studies report compromised cytotoxicity when used as monotherapy and thus combinations with other anti-cancer agents is recommended. Chloroquine is a clinically available anti-malarial agent which has been shown to exhibit anti-cancer activity. In the current study, we questioned whether chloroquine can modulate sunitinib cytotoxicity. We found that chloroquine synergistically augmented sunitinib cytotoxicity on human breast (MCF-7 and T-47D), cervical (Hela), colorectal (Caco-2 and HCT116), hepatocellular (HepG2), laryngeal (HEp-2) and prostate (PC3) cancer cell lines as indicated by combination and concentration reduction indices. These results were also consistent with that of Ehrlich ascites carcinoma (EAC) Swiss albino mice models as confirmed by tumor volume, weight, histopathological examination and PCNA expression. Sunitinib induced autophagy via upregulating beclin-1 expression which was blocked by chloroquine as evidenced by accumulated SQTSM1/p62 level. Furthermore, chloroquine augmented sunitinib-induced apoptosis by decreasing survivin level and increasing caspase 3 activity. Chloroquine also enhanced the antiangiogenic capacity of sunitinib as indicated by decreased CD34 expression and peritoneal/skin angiogenesis. Sunitinib when combined with chloroquine also increased reactive nitrogen species production via increasing inducible nitric oxide synthase expression and nitric oxide level whilst reduced reactive oxygen species production by increasing GSH level, activities of glutathione peroxidase and catalase and reducing lipid peroxides compared to sunitinib-only treated group. Taken together, these findings suggest that chloroquine enhanced sunitinib cytotoxicity in a synergistic manner via inducing apoptosis while switching off autophagic and angiogenic machineries. Nevertheless, further studies are required to elucidate the efficacy and safety profile of such combination.
酪氨酸激酶在肿瘤发生中起着关键作用。虽然马来酸舒尼替尼等酪氨酸激酶抑制剂被用于癌症治疗，但新的研究报告表明，作为单一疗法其细胞毒性受损，因此建议与其他抗癌药物联合使用。氯喹是一种临床可用的抗疟药物，已被证明具有抗癌活性。在本研究中，我们质疑氯喹是否可以调节舒尼替尼的细胞毒性。我们发现氯喹协同增强了舒尼替尼对人乳腺癌（MCF-7 和 T-47D）、宫颈癌（Hela）、结直肠癌（Caco-2 和 HCT116）、肝癌（HepG2）、喉癌（HEp-2）和前列腺癌（PC3）癌细胞系的细胞毒性，表现为组合和浓度降低指数。这些结果也与 Ehrlich 腹水癌（EAC）瑞士白化病小鼠模型一致，通过肿瘤体积、重量、组织病理学检查和 PCNA 表达得到证实。舒尼替尼通过上调 beclin-1 表达诱导自噬，氯喹阻断了这一过程，这一点可以从 SQTSM1/p62 水平的积累中得到证实。此外，氯喹通过降低 survivin 水平和增加 caspase 3 活性来增强舒尼替尼诱导的细胞凋亡。氯喹还通过降低 CD34 表达和腹膜/皮肤血管生成来增强舒尼替尼的抗血管生成能力。与单独使用舒尼替尼相比，舒尼替尼与氯喹联合使用还通过增加诱导型一氧化氮合酶表达和一氧化氮水平来增加活性氮物种的产生，同时通过增加 GSH 水平、谷胱甘肽过氧化物酶和过氧化氢酶的活性以及减少脂质过氧化物来减少活性氧物种的产生。综上所述，这些发现表明，氯喹通过诱导细胞凋亡而关闭自噬和血管生成机制，以协同方式增强舒尼替尼的细胞毒性。然而，需要进一步的研究来阐明这种联合治疗的疗效和安全性。
