RhoB mediates antitumor synergy of combined ixabepilone and sunitinib in human ovarian serous cancer

Prakash Vishnu, Gerardo Colon-Otero, Gregory T. Kennedy, Laura A. Marlow, William P. Kennedy, Kevin J. Wu, Joseph Santoso, John A. Copland

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Abstract

Objective: The aim was to evaluate antitumor activity of the combination of ixabepilone and sunitinib in pre-clinical models of chemotherapy naïve and refractory epithelial ovarian tumors, and to investigate the mechanism of synergy of such drug combination. Methods: HOVTAX2 cell line was derived from a metastatic serous papillary epithelial ovarian tumor (EOC) and a paclitaxel-resistant derivative was established. Dose response curves for ixabepilone and sunitinib were generated and synergy was determined using combination indexes. The molecular mechanism of antitumor synergy was examined using shRNA silencing. Results: The combination of ixabepilone and sunitinib demonstrated robust antitumor synergy in naïve and paclitaxel-resistant HOVTAX2 cell lines due to increased apoptosis. The GTPase, RhoB, was synergistically upregulated in cells treated with ixabepilone and sunitinib. Using shRNA, RhoB was demonstrated to mediate antitumor synergy. These results were validated in two other EOC cell lines. Conclusions: Ixabepilone plus sunitinib demonstrated antitumor synergy via RhoB in naïve and paclitaxel-resistant cells resulting in apoptosis. This study demonstrates a novel mechanism of action leading to antitumor synergy and provides 'proof-of-principle' for combining molecular targeted agents with cytotoxic chemotherapy to improve antitumor efficacy. RhoB could be envisioned as an early biomarker of response to therapy in a planned Phase II clinical trial to assess the efficacy of ixabepilone combined with a receptor tyrosine kinase inhibitor such as sunitinib. To the best of our knowledge, this is the first demonstration of antitumor synergy between these two classes of drugs in EOC and the pivotal role of RhoB in this synergy.

Original languageEnglish (US)
Pages (from-to)589-597
Number of pages9
JournalGynecologic oncology
Volume124
Issue number3
DOIs
StatePublished - Mar 1 2012

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Ovarian Neoplasms
Paclitaxel
Cell Line
Small Interfering RNA
Apoptosis
Drug Therapy
Phase II Clinical Trials
GTP Phosphohydrolases
Cytotoxins
Receptor Protein-Tyrosine Kinases
Drug Combinations
ixabepilone
sunitinib
Neoplasms
Biomarkers
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Oncology
  • Obstetrics and Gynecology

Cite this

Vishnu, P., Colon-Otero, G., Kennedy, G. T., Marlow, L. A., Kennedy, W. P., Wu, K. J., ... Copland, J. A. (2012). RhoB mediates antitumor synergy of combined ixabepilone and sunitinib in human ovarian serous cancer. Gynecologic oncology, 124(3), 589-597. https://doi.org/10.1016/j.ygyno.2011.11.019

RhoB mediates antitumor synergy of combined ixabepilone and sunitinib in human ovarian serous cancer. / Vishnu, Prakash; Colon-Otero, Gerardo; Kennedy, Gregory T.; Marlow, Laura A.; Kennedy, William P.; Wu, Kevin J.; Santoso, Joseph; Copland, John A.

In: Gynecologic oncology, Vol. 124, No. 3, 01.03.2012, p. 589-597.

Research output: Contribution to journalArticle

Vishnu, P, Colon-Otero, G, Kennedy, GT, Marlow, LA, Kennedy, WP, Wu, KJ, Santoso, J & Copland, JA 2012, 'RhoB mediates antitumor synergy of combined ixabepilone and sunitinib in human ovarian serous cancer', Gynecologic oncology, vol. 124, no. 3, pp. 589-597. https://doi.org/10.1016/j.ygyno.2011.11.019
Vishnu, Prakash ; Colon-Otero, Gerardo ; Kennedy, Gregory T. ; Marlow, Laura A. ; Kennedy, William P. ; Wu, Kevin J. ; Santoso, Joseph ; Copland, John A. / RhoB mediates antitumor synergy of combined ixabepilone and sunitinib in human ovarian serous cancer. In: Gynecologic oncology. 2012 ; Vol. 124, No. 3. pp. 589-597.
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AU - Kennedy, Gregory T.

AU - Marlow, Laura A.

AU - Kennedy, William P.

AU - Wu, Kevin J.

AU - Santoso, Joseph

AU - Copland, John A.

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