The andean anticancer herbal product BIRM causes destabilization of androgen receptor and induces caspase-8 mediated-apoptosis in prostate cancer

Nagarajarao Shamaladevi, Shinako Araki, Dominic A. Lyn, Rajnikanth Ayyathurai, Jie Gao, Vinata B Lokeshwar, Hugo Navarrete, Balakrishna L Lokeshwar

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

BIRM is an anticancer herbal formulation from Ecuador. Previous study established its antitumor and antimetastatic activity against prostate cancer models. The activity of BIRM against human prostate cancer (PCa) cells was investigated to uncover its mechanism of antitumor activity. In androgen receptor (AR)-expressing PCa cells BIRM was 2.5-fold (250%) more cytotoxic in presence of androgen (DHT) compared to cells grown in the absence of DHT. In AR-positive cells (LAPC-4 and LNCaP) BIRM caused a dose and time-dependent down-regulation of AR and increased apoptosis. Exposing cells to BIRM did not affect the synthesis of AR and AR promoter activity but increased degradation of AR via proteasome-pathway. BIRM caused destabilization of HSP90-AR association in LAPC-4 cells. It induced apoptosis in PCa cells by activation of caspase-8 via death receptor and FADD-mediated pathways. A synthetic inhibitor of Caspase-8 cleavage (IETD-CHO) aborted BIRM-induced apoptosis. The effect of BIRM on AKT-mediated survival pathway in both AR+ and AR- negative (PC-3 and DU145) showed decreased levels of p-AKTser 473 in all PCa cell lines. BIRM dosed by oral gavage in mice bearing PC-3ML tumors showed selective efficacy on tumor growth; before tumors are established but limited efficacy when treated on existing tumors. Moreover, BIRM inhibited the LNCaP tumor generated by orthotropic implantation into dorsal prostate of nude mice. Partial purification of BIRM by liquid-liquid extraction and further fractionation by HPLC showed 4-fold increased specific activity on PCa cells. These results demonstrate a mechanistic basis of anti-tumor activity of the herbal extract BIRM.

Original languageEnglish (US)
Pages (from-to)84201-84213
Number of pages13
JournalOncotarget
Volume7
Issue number51
DOIs
StatePublished - Jan 1 2016

Fingerprint

Caspase 8
Androgen Receptors
Prostatic Neoplasms
Apoptosis
Neoplasms
Ecuador
Death Domain Receptors
Liquid-Liquid Extraction
Proteasome Endopeptidase Complex
Nude Mice
Androgens
Prostate
Down-Regulation
High Pressure Liquid Chromatography
Cell Line
Survival

Keywords

  • Androgen receptor
  • Anti-cancer herbal preparation
  • Caspase-8
  • Chemoprevention
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology

Cite this

The andean anticancer herbal product BIRM causes destabilization of androgen receptor and induces caspase-8 mediated-apoptosis in prostate cancer. / Shamaladevi, Nagarajarao; Araki, Shinako; Lyn, Dominic A.; Ayyathurai, Rajnikanth; Gao, Jie; Lokeshwar, Vinata B; Navarrete, Hugo; Lokeshwar, Balakrishna L.

In: Oncotarget, Vol. 7, No. 51, 01.01.2016, p. 84201-84213.

Research output: Contribution to journalArticle

Shamaladevi, Nagarajarao ; Araki, Shinako ; Lyn, Dominic A. ; Ayyathurai, Rajnikanth ; Gao, Jie ; Lokeshwar, Vinata B ; Navarrete, Hugo ; Lokeshwar, Balakrishna L. / The andean anticancer herbal product BIRM causes destabilization of androgen receptor and induces caspase-8 mediated-apoptosis in prostate cancer. In: Oncotarget. 2016 ; Vol. 7, No. 51. pp. 84201-84213.
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abstract = "BIRM is an anticancer herbal formulation from Ecuador. Previous study established its antitumor and antimetastatic activity against prostate cancer models. The activity of BIRM against human prostate cancer (PCa) cells was investigated to uncover its mechanism of antitumor activity. In androgen receptor (AR)-expressing PCa cells BIRM was 2.5-fold (250{\%}) more cytotoxic in presence of androgen (DHT) compared to cells grown in the absence of DHT. In AR-positive cells (LAPC-4 and LNCaP) BIRM caused a dose and time-dependent down-regulation of AR and increased apoptosis. Exposing cells to BIRM did not affect the synthesis of AR and AR promoter activity but increased degradation of AR via proteasome-pathway. BIRM caused destabilization of HSP90-AR association in LAPC-4 cells. It induced apoptosis in PCa cells by activation of caspase-8 via death receptor and FADD-mediated pathways. A synthetic inhibitor of Caspase-8 cleavage (IETD-CHO) aborted BIRM-induced apoptosis. The effect of BIRM on AKT-mediated survival pathway in both AR+ and AR- negative (PC-3 and DU145) showed decreased levels of p-AKTser 473 in all PCa cell lines. BIRM dosed by oral gavage in mice bearing PC-3ML tumors showed selective efficacy on tumor growth; before tumors are established but limited efficacy when treated on existing tumors. Moreover, BIRM inhibited the LNCaP tumor generated by orthotropic implantation into dorsal prostate of nude mice. Partial purification of BIRM by liquid-liquid extraction and further fractionation by HPLC showed 4-fold increased specific activity on PCa cells. These results demonstrate a mechanistic basis of anti-tumor activity of the herbal extract BIRM.",
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AU - Ayyathurai, Rajnikanth

AU - Gao, Jie

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