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Cited by 55Prostate Cancer Treatment and ResearchTelomeres, Telomerase, and SenescenceCancer-related Molecular Pathways

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

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Zhang, Yong, Dong, Yinhui, Melkus, Michael W., Yin, Shutao, Tang, Su-Ni, Jiang, Peixin, Pramanik, Kartick, Wu, Wei +5 more·2018·Molecular Cancer Therapeutics
DOI 10.1158/1535-7163.mct-17-1296PMC PMC6668018

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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), 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.

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  • Bufalin induced apoptosis, necroptosis, ferroptosis, autophagy, and senescence through AMPK, RIP1/ROS, DECR1, p62, and p53 pathways.

    “Bufalin induced apoptosis, necroptosis, ferroptosis, autophagy, and senescence through AMPK, RIP1/ROS, DECR1, p62, and p53 pathways5,44–48.”

    From Harnessing artificial intelligence to identify Bufalin as a molecular glue degrader of estrogen receptor alpha (2025) · cites this paper as [48]

    The Results report bufalin-induced apoptosis and increased senescence in LNCaP cells, with p53/p21 signaling promoting senescence. They do not establish necroptosis, ferroptosis, or the AMPK, RIP1/ROS, DECR1, and p62 pathways; the Results also report no increase in the autophagy marker LC-3-II after bufalin exposure. The citation therefore supports only part of the multi-paper sentence. (LLM, conf=0.90)

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Cited by

Sorted by citations

Authors
Zhang, Y., Dong, Y., Melkus, M. W., Yin, S., Tang, S.-N., Jiang, P., Pramanik, K., Wu, W., Kim, S., Ye, M., Hu, H., Lu, J., & Jiang, C.
Affiliations
  • Texas Tech University Health Sciences Center (US)
  • China Agricultural University (CN)
  • Pennsylvania State University (US)
  • Peking University (CN)
  • 1Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas.
Corresponding author
Jiang, Cheng
ORCID
Venue
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research (AACR)
Published
2018-11-01
Volume
17
Issue
11
Pages
2341-2352
ISSN
  • 1535-7163 (ISSN-L)
  • 1538-8514
DOI
10.1158/1535-7163.mct-17-1296
PMC
PMC6668018
OpenAlex
W2889091651
Cited by
55
References
6
Citations by year
2026: 2 · 2025: 7 · 2024: 11 · 2023: 6 · 2022: 8 · 2021: 10 · 2020: 8 · 2019: 3
FWCI
3.96
Type
journal article
Language
en
Open access
Locations
  • Molecular Cancer Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
HHS | NIH | National Cancer Institute (NCI) (R01 CA172169)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
bufalin, prostate cancer, LNCaP cells, cellular senescence, caspase-dependent apoptosis, androgen receptor, p21, G2 cell cycle arrest, xenograft tumor growth, Chansu, anticancer activity
MeSH terms
Animals, Autophagy, Bufanolides, Cardiotonic Agents, Cell Cycle, DNA Damage, Humans, Male, Phenotype, Prostatic Neoplasms, Receptors, Androgen, Stress, Physiological, Biomarkers, Tumor, Up-Regulation, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Mice, SCID, Cellular Senescence, Apoptosis, Caspases, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21

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