Anticancer efficacy of a difluorodiarylidenyl piperidone (HO-3867) in human ovarian cancer cells and tumor xenografts

Karuppaiyah Selvendiran, Liyue Tong, Anna Bratasz, M. Lakshmi Kuppusamy, Shabnam Ahmed, Yazhini Ravi, Nancy J. Trigg, Brian K. Rivera, T. Kalai, K. Hideg, Periannan Kuppusamy

Research output: Contribution to journalArticle

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Abstract

The purpose of this study was to evaluate the anticancer potency and mechanism of a novel difluorodiarylidenyl piperidone (H-4073) and its N-hydroxypyrroline modification (HO-3867) in human ovarian cancer. Studies were done using established human ovarian cancer cell lines (A2870, A2780cDDP, OV-4, SKOV3, PA-1, and OVCAR3) as well as in a murine xenograft tumor (A2780) model. Both compounds were comparably and significantly cytotoxic to A2780 cells. However, HO-3867 showed a preferential toxicity toward ovarian cancer cells while sparing healthy cells. HO-3867 induced G2-M cell cycle arrest in A2780 cells by modulating cell cycle regulatory molecules p53, p21, p27, cyclin-dependent kinase 2, and cyclin, and promoted apoptosis by caspase-8 and caspase-3 activation. It also caused an increase in the expression of functional Fas/CD95 and decreases in signal transducers and activators of transcription 3 (STAT3; Tyr705) and JAK1 phosphorylation. There was a significant reduction in STAT3 downstream target protein levels including Bcl-xL, Bcl-2, survivin, and vascular endothelial growth factor, suggesting that HO-3867 exposure disrupted the JAK/STAT3 signaling pathway. In addition, HO-3867 significantly inhibited the growth of the ovarian xenografted tumors in a dosage-dependent manner without any apparent toxicity. Western blot analysis of the xenograft tumor tissues showed that HO-3867 inhibited pSTAT3 (Tyr705 and Ser727) and JAK1 and increased apoptotic markers cleaved caspase-3 and poly ADP ribose polymerase. HO-3867 exhibited significant cytotoxicity toward ovarian cancer cells by inhibition of the JAK/STAT3 signaling pathway. The study suggested that HO-3867 may be useful as a safe and effective anticancer agent for ovarian cancer therapy.

Original languageEnglish
Pages (from-to)1169-1179
Number of pages11
JournalMolecular Cancer Therapeutics
Volume9
Issue number5
DOIs
Publication statusPublished - May 2010

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Piperidones
Heterografts
Ovarian Neoplasms
Neoplasms
Caspase 3
Cyclin-Dependent Kinase 2
G2 Phase Cell Cycle Checkpoints
STAT3 Transcription Factor
Cyclins
Poly(ADP-ribose) Polymerases
(3,5-bis((4-fluorophenyl)methylidene)-1-((1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)piperidin-4-one)
Caspase 8
Antineoplastic Agents
Vascular Endothelial Growth Factor A
Cell Cycle
Western Blotting
Phosphorylation
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Selvendiran, K., Tong, L., Bratasz, A., Lakshmi Kuppusamy, M., Ahmed, S., Ravi, Y., ... Kuppusamy, P. (2010). Anticancer efficacy of a difluorodiarylidenyl piperidone (HO-3867) in human ovarian cancer cells and tumor xenografts. Molecular Cancer Therapeutics, 9(5), 1169-1179. https://doi.org/10.1158/1535-7163.MCT-09-1207

Anticancer efficacy of a difluorodiarylidenyl piperidone (HO-3867) in human ovarian cancer cells and tumor xenografts. / Selvendiran, Karuppaiyah; Tong, Liyue; Bratasz, Anna; Lakshmi Kuppusamy, M.; Ahmed, Shabnam; Ravi, Yazhini; Trigg, Nancy J.; Rivera, Brian K.; Kalai, T.; Hideg, K.; Kuppusamy, Periannan.

In: Molecular Cancer Therapeutics, Vol. 9, No. 5, 05.2010, p. 1169-1179.

Research output: Contribution to journalArticle

Selvendiran, K, Tong, L, Bratasz, A, Lakshmi Kuppusamy, M, Ahmed, S, Ravi, Y, Trigg, NJ, Rivera, BK, Kalai, T, Hideg, K & Kuppusamy, P 2010, 'Anticancer efficacy of a difluorodiarylidenyl piperidone (HO-3867) in human ovarian cancer cells and tumor xenografts', Molecular Cancer Therapeutics, vol. 9, no. 5, pp. 1169-1179. https://doi.org/10.1158/1535-7163.MCT-09-1207
Selvendiran, Karuppaiyah ; Tong, Liyue ; Bratasz, Anna ; Lakshmi Kuppusamy, M. ; Ahmed, Shabnam ; Ravi, Yazhini ; Trigg, Nancy J. ; Rivera, Brian K. ; Kalai, T. ; Hideg, K. ; Kuppusamy, Periannan. / Anticancer efficacy of a difluorodiarylidenyl piperidone (HO-3867) in human ovarian cancer cells and tumor xenografts. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 5. pp. 1169-1179.
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