(S)-Crizotinib

(S)-Crizotinib, a (S)-enantiomer of crizotinib, is a potent and selective MTH1 (mutT homologue) inhibitor with an IC50 of 330 nM. (S)-Crizotinib disrupts nucleotide pool homeostasis via MTH1 inhibition, induces an increase in DNA single strand breaks, activates DNA repair in human colon carcinoma cells, and effectively suppresses tumour growth in animal models[1].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

IC50: 330 nM (MTH1)[1]

(S)-crizotinib (0.625-80 μM; 24 hours) decreases the viability of NCI-H460, H1975 and A549 cells with IC50 values of 14.29, 16.54 and 11.25 μM, respectively[2]. (S)-crizotinib (10-30 μM; 24 hours) induces NCI-H460, H1975 and A549 cells apoptosis[2]. (S)-crizotinib (10-30 μM; 24 hours) decreases Bcl-2: Bax ratio. (S)-crizotinib decreases B cell lymphoma 2 (Bcl-2), and Bcl-2 associated protein x (Bax) is either unaltered (H460 cells) or shows an increase (H1975 cells)[2]. (S)-Crizotinib induces apoptosis in human non-small cell lung cancer (NSCLC) cells by activating ROS-dependent ER stress apoptotic pathway independent of mutT homologue (MTH1)[2]. Cell Viability Assay[2] Cell Line: NSCLC cells, NCI-H460, H1975 and A549 cells Concentration: 0.625, 1.25, 2.5, 5, 10, 20, 40, 60, 80 μM Incubation Time: 24 hours Result: Decreased the viability of NCI-H460, H1975 and A549 cells with IC50 values of 14.29, 16.54 and 11.25 μM, respectively. Apoptosis Analysis[2] Cell Line: NSCLC cells, NCI-H460, H1975 and A549 cells Concentration: 10, 20 or 30 μM Incubation Time: 24 hours Result: Induced cells apoptosis. Western Blot Analysis[2] Cell Line: NSCLC cells, NCI-H460, H1975 and A549 cells Concentration: 10, 20 or 30 μM Incubation Time: 24 hours Result: Decreased Bcl-2: Bax ratio.

(S)-crizotinib (7.5 or 15 mg/kg; intraperitoneal injections; once daily for 10 days) results in significant reductions in both tumor volume and tumor weight[2]. Animal Model: Five-week-old, athymic BALB/c nu/nu female mice (17-19 g) with NCI-H460 cells[2] Dosage: 7.5 or 15 mg/kg Administration: Intraperitoneal injections; once daily for 10 days Result: Resulted in significant reductions in both tumor volume and tumor weight.

[1]. Huber KV, et al. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Nature. 2014 Apr 10;508(7495):222-7.

[2]. Dai X, et al. (S)-crizotinib induces apoptosis in human non-small cell lung cancer cells by activating ROS independent of MTH1. J Exp Clin Cancer Res. 2017 Sep 7;36(1):120.