ELR-CXC chemokine antagonism and cisplatin co-treatment additively reduce H22 hepatoma tumor progression and ameliorate cisplatin-induced nephrotoxicity

Abstract

Cisplatin (cis-diamminedichloroplatinum) is one of the most commonly used agents for the chemotherapy of various types of cancers, but its use is limited by its dose-dependent side-effects (e.g., nephrotoxicity). The ELR-CXC chemokines are potent tumor growth, metastatic and angiogenic factors and can foster tumor resistance to chemotherapeutic agents. They are also potent proinflammatory agents. The aim of the present study was to evaluate the added effects of combining cisplatin chemotherapy with ELR-CXC chemokine antagonism in a mouse H22 hepatoma cancer cell model. The mice were injected with tumor cells and were then treated with cisplatin (12.5 or 2 mg/kg doses), either alone or together with the chemokine antagonist CXCL8 (3-72) K11R/G31P (G31P) (50 μg/kg). At varying time-points renal function was examined using blood urea nitrogen (BUN) and serum creatinine (SCr) as read-outs for the toxic effects of cisplatin, while tumor growth and metastasis were assessed as endpoints. High-dose cisplatin therapy reduced the tumor burden by 52%, while co-delivery of G31P further augmented the tumor growth-suppressive effects of this dose of cisplatin to 71%; G31P by itself and low-dose cisplatin reduced the tumor burden by 19 and 39%, respectively. G31P also reduced the nephrotoxic effects of high-dose cisplatin to the effects observed in the low-dose cisplatin-treated animals. These data confirm the beneficial effects of combined cisplatin chemotherapy and ELR-CXC chemokine anatagonism in the context of both tumor progression and adverse side-effects.