Chloroquine, a worldwide used drug in treatment of malaria, rheumatoid and other human diseases, has recently been focused as a potential anti-cancer drug as well as a chemo-sensitizer when given in combination with other anti-cancer drugs. In cancer treatment, chloroquine possesses a major potential therapeutic advantage in which it specifically targets cancer cells. Unfortunately, however, its anticancer activity is rather low. To further improve its efficacy and specificity in killing cancer cells, we created and characterized several chloroquine derivatives using a hybrid pharmacophore approach, which led us to identify VR23 as the most promising compound. Our in-vitro model of cancer cells shows that VR23 functions as a novel proteasome inhibitor. It also deregulates activity of cyclin E and other centrosomal proteins, resulting in induction of multiple centrosome amplification, abnormal spindle formation, uneven cytokinesis, irreversible mitotic arrests, and eventually apoptosis. These VR23-induced phenomena occur in cancer-specific manner and cause massive death in a variety of cancer cell types. The treatment of engrafted animals with VR23 (30 mg/kg) twice per week for three weeks effectively inhibits tumor growth. Interestingly, administration of VR23 following 24 hours pre-treatment with paclitaxel (20mg/kg/week) enhances paclitaxel's anti-tumor activity by 70%. Our histological data shows that VR23 causes substantial decrease in mitotic index, inhibition of tumor infiltration into surrounding tissues and remarkable reduction of tumor cell proliferation and angiogenesis. Most importantly, VR23 shows very low toxicity to vital organs (liver, spleen, kidney and lung) of non-tumor-bearing nude mice. In addition, VR23 seems to reduce paclitaxel-induced toxicity when used in combination. Taken together, VR23, our novel chloroquine derivative and newly discovered proteasome inhibitor, appears to be an effective and safe anticancer therapeutic alone or in combination with other anticancer agents.

Citation Format: Hai-Yen Thi Vu, Sheetal Pundir, Raja V. Solomon, Hoyun Lee. Anticancer effects and mechanism of VR23, a novel chloroquine derivative. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4545. doi:10.1158/1538-7445.AM2014-4545