VR23 is an effective proteasome inhibitor, with IC50 values of 3 μmol/L, 1 nmol/L, and 50-100 nmol/L to inhibit activities of caspase-like proteasomes, trypsin-like proteasomes, and chymotrypsin-like proteasomes, respectively [1].
As a regulator, the ubiquitin-proteasome system is important for cell growth and apoptosis [2]. The ubiquitin-proteasome pathway is critical in the regulated degradation of proteins involved in tumor growth and cell cycle control [3].
Treatment with VR23 made cancer cells undergo an abnormal centrosome amplification cycle. This cycle was caused by the accumulation of ubiquitinated cyclin E. Bortezomib is clinically approved as a chymotrypsin-like proteasome inhibitor. VR23 in combinations with bortezomib, caused a synergistic effect in killing multiple myeloma cells. This synergistic effect was also effective to myeloma cells resistant to bortezomib [1].
In vivo, VR23 was effective in controlling metastatic breast cancer cells and multiple myelomas [1]. In engrafted animals, the treatment with VR23 at 30 mg/kg twice per week for three weeks inhibited tumor growth effectively. Following 24 hours pre-treatment with paclitaxel at 20mg/kg/week, the administration of VR23 enhanced the anti-tumor activity of paclitaxel by 70%. Histological data showed that VR23 substantially decreased mitotic index, inhibited tumor infiltration into surrounding tissues and remarkably reduced tumor cell proliferation and angiogenesis [4].
References:
[1]. Pundir S, Vu HY, Solomon VR, et al. VR23: A Quinoline-Sulfonyl Hybrid Proteasome Inhibitor That Selectively Kills Cancer via Cyclin E-Mediated Centrosome Amplification. Cancer research, 2015, 75(19): 4164-4175.
[2]. Almond JB, Cohen GM. The proteasome: a novel target for cancer chemotherapy. Leukemia, 2002, 16(4): 433-443.
[3]. Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer research, 1999, 59(11): 2615-2622.
[4]. Vu HYT, Pundir S, Solomon RV, et al. Anticancer effects and mechanism of VR23, a novel chloroquine derivative. Cancer Research, 2014, 74(19 Supplement): 4545-4545.
