Role of P53-Senescence Induction in Suppression of LNCaP Prostate Cancer Growth by Cardiotonic Compound Bufalin.

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), G2 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. Mol Cancer Ther; 17(11); 2341-52. ©2018 AACR.

• Authors: 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 17 Issue 11 Pg. 2341-2352 (11 2018) ISSN: 1538-8514 [Electronic] United States
• PMID: 30166403 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• Bufanolides
• Cardiotonic Agents
• Cyclin-Dependent Kinase Inhibitor p21
• Receptors, Androgen
• Tumor Suppressor Protein p53
• Caspases
• bufalin

Topics

• Animals
• Apoptosis (drug effects, genetics)
• Autophagy (drug effects, genetics)
• Biomarkers, Tumor (metabolism)
• Bufanolides (chemistry, pharmacology)
• Cardiotonic Agents (chemistry, pharmacology)
• Caspases (metabolism)
• Cell Cycle (drug effects, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cellular Senescence (drug effects, genetics)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• DNA Damage
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Mice, SCID
• Phenotype
• Prostatic Neoplasms (genetics, pathology)
• Receptors, Androgen (metabolism)
• Stress, Physiological (drug effects)
• Tumor Suppressor Protein p53 (metabolism)
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays