Abstract LB-017: Minnelide reduces castration-resistant and enzalutamide-resistant prostate cancer via downregulation of androgen receptor-mediated signaling

Abstract

Prostate cancer is the second leading cause of cancer death in men in western countries. Advanced prostate cancer is often resistant to hormonal treatment and systemic chemotherapy has limited efficacy. Androgen receptor (AR), a ligand dependent transcription factor plays pivotal role in the development and progression of prostate cancer. While majority of prostate cancers are initially androgen dependent and respond to androgen ablation therapy, most patients eventually recur with more aggressive castration-resistant prostate cancer (CRPC) where AR signaling is reactivated even in the absence of androgen stimulation. Therefore developing novel chemotherapeutic agents for castrate resistant prostate cancer (CRPC) treatment is critical to improve survival in men with CRPC. Triptolide, a diterpene triepoxide isolated from a chinese herb, is extremely effective against several cancers like pancreatic cancer, colorectal cancer and liver cancer both in vivo and in vitro. The water-soluble pro-drug of triptolide, Minnelide, downregulates HSP70 via inhibition of the activity of transcription factor Sp1. Since both Sp1 and HSP70 have been reported to be critical in functionality of AR, we assessed therapeutic potential of Minnelide on androgen dependent, CRPC in vitro and in vivo. Triptolide treatment resulted in dose- and time-dependent cell death in an androgen dependent cell line LNCaP, CRPC cell line C4-2 and enzalutamide resistant CRPC tumor cell line 22RV1. Triptolide treatment decreased expression of AR full length, AR splice variants and its downstream targets (PSA, NKX3.1) at the mRNA and protein levels. Further, reporter assay with AR responsive elements showed that triptolide decreased transcriptional activity of AR. Expression levels of Sp1 and HSP70 were also reduced following treatment with triptolide these cell lines. To test the efficacy of Minnelide in vivo, male athymic nude mice were castrated 7 days prior to implantation of enzalutamide resistant CRPC (22RV1) cells subcutaneously. The animals received daily intraperitoneal injection of Minnelide and tumor volume was measured weekly until tumor size reached 2cm3.Mice receiving daily injection of Minnelide had significantly smaller tumors than controls as early as two week of treatment (p = 0.008). Triptolide therapy inhibited enzalutamide resistant CRPC growth both in vitro and in vivo. Further, our studies for the first time showed that triptolide induces prostate tumor cell death by reducing expression of both full length AR and AR splice variants in a similar manner. Citation Format: Sumit Isharwal, Shrey Modi, Usman Barlass, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee, Badrinath Konety. Minnelide reduces castration-resistant and enzalutamide-resistant prostate cancer via downregulation of androgen receptor-mediated signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-017. doi:10.1158/1538-7445.AM2015-LB-017

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“…Triptolide suppresses the proliferation and promotes apoptotic cell death in various cancers, especially hard-to-treat types, including prostate and pancreatic cancers. Prostate and pancreatic cancers are the third and fourth leading causes of cancer death in western countries, respectively ( Isharwal et al, 2015 ). Treatment with triptolide induces the nuclear accumulation of p53 and apoptotic cell death in primary cultures of human prostatic epithelial cells ( Kiviharju et al, 2002 ).…”

Therapeutic Potential of Certain Terpenoids as Anticancer Agents: A Scoping Review

“…The mechanism of action of this compound involved the reduction of androgen receptors and inhibition of the downstream targets, such as prostate-specific antigen (PSA) and NKX3.1 prostatic tumor suppressor gene. Further investigations showed that triptolide reduced the transcription activity of androgen receptors by inhibiting Sp1 (transcription factor) and HSP70 expression [ 231 ]. In addition, the sensitization effect of triptolide on pancreatic cancer cells toward gemcitabine was suggested through mitochondrial-induced apoptosis and inhibition of HSP27 [ 186 ].…”