3,3′-Diindolylmethane Enhances Taxotere-Induced Apoptosis in Hormone-Refractory Prostate Cancer Cells through Survivin Down-regulation

Abstract

Survivin, a member of inhibitor of apoptosis family, is associated with both prostate cancer progression and drug resistance. Therefore, we hypothesized that survivin may play a potentially important role in hormone-refractory prostate cancer (HRPC) and bone metastatic disease; thus, targeting of survivin signaling could enhance therapeutic efficacy in prostate cancer. 3,3 ¶-Diindolylmethane (DIM) has been known to have cancer chemoprevention activity. However, no information is available regarding the down-regulation of survivin by DIM, which could result in the chemosensitization of HRPC cells to Taxotere-induced killing. We investigated the effect of DIM alone or in combination with Taxotere using LNCaP and C4-2B prostate cancer cells. We observed that DIM enhanced Taxotere-induced apoptotic death in both cell lines. These enhancing effects were related to a decrease in survivin expression as well as androgen receptor and nuclear factor-KB (NF-KB) DNA-binding activity. We also found that knockdown of survivin expression by small interfering RNA transfection increased DIM-induced cell growth inhibition and apoptosis, whereas overexpression of survivin by cDNA transfection abrogated DIM-induced cell growth inhibition and apoptosis in both prostate cancer cells. Importantly, luciferase assays showed a significant reduction of survivin-Luc and NF-KB-Luc activity in prostate cancer cells exposed to DIM and Taxotere. Furthermore, combination treatment significantly inhibited C4-2B bone tumor growth, and the results were correlated with the down-regulation of survivin. From these results, we conclude that inactivation of survivin by DIM enhanced the therapeutic efficacy of Taxotere in prostate cancer in general, which could be useful for the treatment of HRPC and metastatic prostate cancer. [Cancer Res 2009;69(10):4468-75]

Synergistic anti‐tumor activity of isochaihulactone and paclitaxel on human lung cancer cells

“…Paclitaxel and K8 are implicated in the regulation of various signaling pathways involved in proliferation, differentiation, and apoptosis (Ambrosini et al, 1998;Olie et al, 2000;Bacus et al, 2001;Liu and Sun, 2003;Chen and Wong, 2008;Rahman et al, 2009). Existing data indicate that the MAPK pathway is related to paclitaxel-or K8-induced cell death in three different human cancer cell lines: HeLa cervical carcinoma, MCF7 breast cancer, and A431 squamous carcinoma cells (Bacus et al, 2001).…”

Pathways of chemotherapy resistance in castration-resistant prostate cancer

“…An inhibitor of XIAP improves response to cisplatin by increasing caspase 3 activity in prostate cancer cell lines normally resistant to platinum therapy (DU145; Amantana et al 2004). Survivin inhibition across several prostate cancer cell lines (LNCaP, DU145, PC3, C42B) increases sensitivity to docetaxel and etoposide (Hayashi et al 2005, Rahman et al 2009), whereas survivin overexpression increases paclitaxel resistance both in vitro and in vivo (Zhang et al 2005b). In DU145 and PC3 xenografts, survivin inhibition either via an adenoviral anti-sense DNA vector or via a small molecule inhibitor leads to significant tumour regression alone and enhances the response to docetaxel and etoposide (Hayashi et al 2005, Nakahara et al 2007.…”

Indoles as anticancer agents

“…CIAPs, X-chromosome linked inhibitor of apoptose protein (XIAP) and survival, (c): up-regulation of pro-apoptotic factors such as Bax gene, (d): liberation of mitochondrial cytochrome C in addition to stimulating of caspase-9 and caspase-3 [45] , and (e): inhibition of the NF-k B signaling pathway [46][47][48][49][50][51] . A vast number of diverse mechanisms of apoptosis induction by indoles have also been reported [52][53][54][55][56] . Figure 8 demonstrates the extrinsic and the intrinsic pathways of apoptosis (programmed cell death).…”