Description
VR23 is a chloroquine derivative that functions as a proteasome inhibitor (IC
50s = 1 nM, 50-100 nM, and 3 μM for trypsin-like, chymotrypsin-like, and caspase-like proteasomes, respectively). It also deregulates the activity of cyclin E and other centrosomal proteins, resulting in the induction of multiple centrosome amplification, abnormal spindle formation, uneven cytokinesis, irreversible mitotic arrest, and eventually apoptosis that is specific to cancer cells. In combination with the chymotrypsin-like proteasome inhibitor bortezomib , VR23 can produce a synergistic effect in killing multiple myeloma cells, including those that are resistant to bortezomib.
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.
