title: Chloroquine synergizes sunitinib cytotoxicity via modulating autophagic, apoptotic and angiogenic machineries.
abstract: 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.
authors.affiliation: Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Amal Kamal
authors.initials: AK
authors.lastname: Abdel-Aziz
authors.affiliation: Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
authors.forename: Samia
authors.initials: S
authors.lastname: Shouman
authors.affiliation: Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
authors.forename: Ebtehal
authors.initials: E
authors.lastname: El-Demerdash
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elgendy
authors.affiliation: Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. Electronic address: abnaim@pharma.asu.edu.eg.
authors.forename: Ashraf B
authors.initials: AB
authors.lastname: Abdel-Naim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D018938:Caco-2 Cells; D002286:Carcinoma, Ehrlich Tumor / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D002738:Chloroquine; D000077210:Sunitinib
keywords: Angiogenesis; Apoptosis; Autophagy; Chloroquine; Oxidative stress; Sunitinib