Tumor growth attenuating effect of celastrol in systemic malignancies.

Abstract

Celastrol (CLL) attenuates and restricts tumor growth1 in a number of systemic malignancies. CLL has an inhibitory effect on tumor growth in hepatic malignancies. It mediates this role in part by down-regulating MMP-2 and MMP-9 expression. Rajendran et al. have recently shown that in addition, CLL attenuates Janus-activated kinase-1 and Janus-activated kinase-2 activation.2 At the same time, CLL has a suppressive effect on Akt activation. As a result, intra-tumoral apoptosis is markedly augmented. These changes are dose-dependent and have recently been confirmed in HepG2 and Huh7 cell lines. c-Src activation is inhibited concurrently. Li et al. have recently demonstrated that in addition, CLL attenuates miR-224 expression.3 As a result, tumor cell migration and invasion is markedly impaired. At the same time, CLL has an inhibitory effect on STAT3 activation. As a result, tumor cell proliferation is markedly attenuated. Yan et al. have recently demonstrated that CLL also enhances the cytotoxic effects of other agents such as lapatinib.4 In addition, CLL has a negative impact on NF-κB activation thereby further mitigating tumor growth in hepatocellular carcinomas.5 CLL has a negative impact on tumor expansion in prostatic malignancies. It mediates this role in part by up-regulating Noxa expression. p50 and p65 expression is significantly attenuated. As a result, intra-tumoral apoptosis is markedly augmented. Dai et al. have recently shown that in addition, CLL has an inhibitory effect on NF-kB activity.6 These changes have recently been confirmed in VCaP, PC-3, DU145 and CL1 cells. Recent data suggests that CLL is especially effective in mitigating tumor growth in prostate carcinomas that express the TMPRSS2/ERG fusion gene. In addition, CLL has a positive impact on Mcl-1 cleavage. Shao et al. have recently shown that CLL also targets androgen receptors. Tumor cell migration and invasion is impaired concurrently.7 At the same time, G0/G1 phase arrest is seen. In addition, CLL accentuates PARP cleavage. Chiang et al. have recently demonstrated that concurrently, CLL has a negative impact on IL-6 secretion.8 Besides the above mentioned changes, CLL also attenuates IκBα degradation thereby further abrogating tumor growth in prostate carcinomas. As is obvious from the above discussion, CLL mitigates tumor growth in a number of different systemic malignancies. CLL has shown considerable promise so far as an anti-neoplastic agent and further research to harness its anti-neoplastic properties is urgently needed.