HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells

Brent J. Tierney, Georgia A. McCann, David E. Cohn, Eric Eisenhauer, Meryl Sudhakar, Periannan Kuppusamy, K. Hideg, Karuppaiyah Selvendiran

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

BRCA1 plays an important role in DNA damage and repair, homologous recombination, cell cycle regulation and apoptosis. BRCA-mutated ovarian cancer often presents at an advanced stage, however, tend to have better response to platinumbased chemotherapy as compared with sporadic cases of epithelial ovarian cancer (EOC). In spite of this, most patients will develop a recurrence and eventually succumb to the disease. Preclinical studies are currently investigating natural compounds and their analogs for tumor-directed targets in ovarian cancer. The aim of this study is to investigate whether the STAT3 inhibitor HO-3867, a novel curcumin analog, has a therapeutic effect on BRCA1-mutated ovarian cancer. Our novel agent, HO-3867 and a commercial STAT3 inhibitor, STATTIC, significantly inhibited BRCA-mutated ovarian cancer cells in vitro in a dose- and time-dependent manner. BRCA-mutated ovarian cancer cells treated with HO-3867 exhibited a significant degree of apoptosis with elevated levels of cleaved caspase-3, caspase-7 and PA RP. HO-3867 treatment induced more reactive oxygen species (ROS) in BRCA-mutated cells compared with wild-type cells, however, there was no increased ROS when benign ovarian surface epithelial cells were treated with HO-3867. BRCA1-mutated cancer cells had higher expression of Tyrosine-phosphorylated STAT3 (pTyr705) as compared with other STAT proteins. Furthermore, treatment of these cells with HO-3867 resulted in decreased expression of pTyr705 and its downstream targets cyclin D1, Bcl-2 and survivin. In addition, overexpression of STAT3 cDNA provided resistance to HO-3867-induced apoptosis. Our results show that HO-3867, a potent STAT3 inhibitor, may have a role as a biologically targeted agent for BRCA1-mutated cancers either as an adjunct to cytotoxic chemotherapy or as a single agent.

Original languageEnglish
Pages (from-to)766-775
Number of pages10
JournalCancer Biology and Therapy
Volume13
Issue number9
DOIs
Publication statusPublished - Jul 2012

Fingerprint

Ovarian Neoplasms
Apoptosis
Reactive Oxygen Species
Caspase 7
Drug Therapy
Neoplasms
Curcumin
(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)
Homologous Recombination
Cyclin D1
Therapeutic Uses
Caspase 3
DNA Repair
DNA Damage
Tyrosine
Cell Cycle
Complementary DNA
Epithelial Cells
Recurrence
Therapeutics

Keywords

  • Apoptosis
  • BRCA1
  • Curcumin analog
  • HO-3867
  • Ovarian cancer
  • STAT3

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

Cite this

Tierney, B. J., McCann, G. A., Cohn, D. E., Eisenhauer, E., Sudhakar, M., Kuppusamy, P., ... Selvendiran, K. (2012). HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells. Cancer Biology and Therapy, 13(9), 766-775. https://doi.org/10.4161/cbt.20559

HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells. / Tierney, Brent J.; McCann, Georgia A.; Cohn, David E.; Eisenhauer, Eric; Sudhakar, Meryl; Kuppusamy, Periannan; Hideg, K.; Selvendiran, Karuppaiyah.

In: Cancer Biology and Therapy, Vol. 13, No. 9, 07.2012, p. 766-775.

Research output: Contribution to journalArticle

Tierney, BJ, McCann, GA, Cohn, DE, Eisenhauer, E, Sudhakar, M, Kuppusamy, P, Hideg, K & Selvendiran, K 2012, 'HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells', Cancer Biology and Therapy, vol. 13, no. 9, pp. 766-775. https://doi.org/10.4161/cbt.20559
Tierney, Brent J. ; McCann, Georgia A. ; Cohn, David E. ; Eisenhauer, Eric ; Sudhakar, Meryl ; Kuppusamy, Periannan ; Hideg, K. ; Selvendiran, Karuppaiyah. / HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells. In: Cancer Biology and Therapy. 2012 ; Vol. 13, No. 9. pp. 766-775.
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