Role of p53-senescence induction in suppression of LNCaP prostate cancer growth by cardiotonic compound bufalin

Yong Zhang, Yinhui Dong, Michael W. Melkus, Shutao Yin, Su Ni Tang, Peixin Jiang, Kartick Pramanik, Wei Wu, Sangyub Kim, Min Ye, Hongbo Hu, Junxuan Lu, Cheng Jiang

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Bufalin is a major cardiotonic compound in the traditional Chinese medicine, Chansu, prepared from toad skin secretions. Cell culture studies have suggested an anticancer potential involving multiple cellular processes, including differentiation, apoptosis, senescence, and angiogenesis. In prostate cancer cell models, P53-dependent and independent caspase-mediated apoptosis and androgen receptor (AR) antagonism have been described for bufalin at micromolar concentrations. Because a human pharmacokinetic study indicated that single nanomolar bufalin was safely achievable in the peripheral circulation, we evaluated its cellular activity within range with the AR-positive and P53 wild-type human LNCaP prostate cancer cells in vitro. Our data show that bufalin induced caspase-mediated apoptosis at 20 nmol/L or higher concentration with concomitant suppression of AR protein and its best-known target, PSA and steroid receptor coactivator 1 and 3 (SRC-1, SRC-3). Bufalin exposure induced protein abundance of P53 (not mRNA) and P21CIP1 (CDKN1A), G 2 arrest, and increased senescence-like phenotype (SA-galactosidase). Small RNAi knocking down of P53 attenuated bufalin-induced senescence, whereas knocking down of P21CIP1 exacerbated bufalin-induced caspase-mediated apoptosis. In vivo, daily intraperitoneal injection of bufalin (1.5 mg/kg body weight) for 9 weeks delayed LNCaP subcutaneous xenograft tumor growth in NSG SCID mice with a 67% decrease of final weight without affecting body weight. Tumors from bufalin-treated mice exhibited increased phospho-P53 and SA-galactosidase without detectable caspase-mediated apoptosis or suppression of AR and PSA. Our data suggest potential applications of bufalin in therapy of prostate cancer in patients or chemo-interception of prostate precancerous lesions, engaging a selective activation of P53 senescence.

Original languageEnglish (US)
Pages (from-to)2341-2352
Number of pages12
JournalMolecular cancer therapeutics
Volume17
Issue number11
DOIs
StatePublished - Nov 2018

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Cardiotonic Agents
Prostatic Neoplasms
Growth
Androgen Receptors
Caspases
Apoptosis
Galactosidases
Nuclear Receptor Coactivator 3
Nuclear Receptor Coactivator 1
Body Weight
bufalin
SCID Mice
Chinese Traditional Medicine
RNA Interference
Intraperitoneal Injections
Heterografts
Anura
Prostate
Neoplasms
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Zhang, Yong ; Dong, Yinhui ; Melkus, Michael W. ; Yin, Shutao ; Tang, Su Ni ; Jiang, Peixin ; Pramanik, Kartick ; Wu, Wei ; Kim, Sangyub ; Ye, Min ; Hu, Hongbo ; Lu, Junxuan ; Jiang, Cheng. / Role of p53-senescence induction in suppression of LNCaP prostate cancer growth by cardiotonic compound bufalin. In: Molecular cancer therapeutics. 2018 ; Vol. 17, No. 11. pp. 2341-2352.
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abstract = "Bufalin is a major cardiotonic compound in the traditional Chinese medicine, Chansu, prepared from toad skin secretions. Cell culture studies have suggested an anticancer potential involving multiple cellular processes, including differentiation, apoptosis, senescence, and angiogenesis. In prostate cancer cell models, P53-dependent and independent caspase-mediated apoptosis and androgen receptor (AR) antagonism have been described for bufalin at micromolar concentrations. Because a human pharmacokinetic study indicated that single nanomolar bufalin was safely achievable in the peripheral circulation, we evaluated its cellular activity within range with the AR-positive and P53 wild-type human LNCaP prostate cancer cells in vitro. Our data show that bufalin induced caspase-mediated apoptosis at 20 nmol/L or higher concentration with concomitant suppression of AR protein and its best-known target, PSA and steroid receptor coactivator 1 and 3 (SRC-1, SRC-3). Bufalin exposure induced protein abundance of P53 (not mRNA) and P21CIP1 (CDKN1A), G 2 arrest, and increased senescence-like phenotype (SA-galactosidase). Small RNAi knocking down of P53 attenuated bufalin-induced senescence, whereas knocking down of P21CIP1 exacerbated bufalin-induced caspase-mediated apoptosis. In vivo, daily intraperitoneal injection of bufalin (1.5 mg/kg body weight) for 9 weeks delayed LNCaP subcutaneous xenograft tumor growth in NSG SCID mice with a 67{\%} decrease of final weight without affecting body weight. Tumors from bufalin-treated mice exhibited increased phospho-P53 and SA-galactosidase without detectable caspase-mediated apoptosis or suppression of AR and PSA. Our data suggest potential applications of bufalin in therapy of prostate cancer in patients or chemo-interception of prostate precancerous lesions, engaging a selective activation of P53 senescence.",
author = "Yong Zhang and Yinhui Dong and Melkus, {Michael W.} and Shutao Yin and Tang, {Su Ni} and Peixin Jiang and Kartick Pramanik and Wei Wu and Sangyub Kim and Min Ye and Hongbo Hu and Junxuan Lu and Cheng Jiang",
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Zhang, Y, Dong, Y, Melkus, MW, Yin, S, Tang, SN, Jiang, P, Pramanik, K, Wu, W, Kim, S, Ye, M, Hu, H, Lu, J & Jiang, C 2018, 'Role of p53-senescence induction in suppression of LNCaP prostate cancer growth by cardiotonic compound bufalin', Molecular cancer therapeutics, vol. 17, no. 11, pp. 2341-2352. https://doi.org/10.1158/1535-7163.MCT-17-1296

Role of p53-senescence induction in suppression of LNCaP prostate cancer growth by cardiotonic compound bufalin. / Zhang, Yong; Dong, Yinhui; Melkus, Michael W.; Yin, Shutao; Tang, Su Ni; Jiang, Peixin; Pramanik, Kartick; Wu, Wei; Kim, Sangyub; Ye, Min; Hu, Hongbo; Lu, Junxuan; Jiang, Cheng.

In: Molecular cancer therapeutics, Vol. 17, No. 11, 11.2018, p. 2341-2352.

Research output: Contribution to journalArticle

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AU - Zhang, Yong

AU - Dong, Yinhui

AU - Melkus, Michael W.

AU - Yin, Shutao

AU - Tang, Su Ni

AU - Jiang, Peixin

AU - Pramanik, Kartick

AU - Wu, Wei

AU - Kim, Sangyub

AU - Ye, Min

AU - Hu, Hongbo

AU - Lu, Junxuan

AU - Jiang, Cheng

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