Sensitization of head and neck cancer to cisplatin through the use of a novel curcumin analog

Waleed M. Abuzeid, Samantha Davis, Alice L. Tang, Lindsay Saunders, J. Chadwick Brenner, Jiayuh Lin, James R. Fuchs, Emily Light, Carol R. Bradford, Mark E.P. Prince, Thomas E. Carey

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Objective: To determine whether a novel small molecule inhibitor derived from curcumin (FLLL32) that targets signal transducer and activator of transcription (STAT) 3 would induce cytotoxic effects in STAT3-dependent head and neck squamous cell cancer (HNSCC) cells and would sensitize tumors to cisplatin. Design: Basic science. Two HNSCC cell lines, UM-SCC-29 and UM-SCC-74B, were characterized for cisplatin [cis-diammineplatinum(II) dichloride] sensitivity. Baseline expression of STAT3 and other apoptosis proteins was determined. The FLLL32 50% inhibitory concentration (IC 50) dose was determined for each cell line, and the effect of FLLL32 treatment on the expression of phosphorylated STAT3 and other key proteins was elucidated. The antitumor efficacy of cisplatin, FLLL32, and combination treatment was measured. The proportion of apoptotic cells after cisplatin, FLLL32, or combination therapy was determined. Results: The UM-SCC-29 cell line is cisplatin resistant, and the UM-SCC-74B cell line is cisplatin sensitive. Both cell lines express STAT3, phosphorylated STAT3 (pSTAT3), and key apoptotic proteins. FLLL32 downregulates the active form of STAT3, pSTAT3, in HNSCC cells and induces a potent antitumor effect. FLLL32, alone or with cisplatin, increases the proportion of apoptotic cells. FLLL32 sensitized cisplatin-resistant cancer cells, achieving an equivalent tumor kill with a 4-fold lower dose of cisplatin. Conclusions: FLLL 32 monotherapy induces a potent antitumor effect and sensitizes cancer cells to cisplatin, permitting an equivalent or improved antitumor effect at lower doses of cisplatin. Our results suggest that FLLL32 acts by inhibiting STAT3 phosphorylation, reduced survival signaling, increased susceptibility to apoptosis, and sensitization to cisplatin.

Original languageEnglish (US)
Pages (from-to)499-507
Number of pages9
JournalArchives of Otolaryngology - Head and Neck Surgery
Volume137
Issue number5
DOIs
Publication statusPublished - May 1 2011

    Fingerprint

ASJC Scopus subject areas

  • Surgery
  • Otorhinolaryngology

Cite this