Abuzeid Waleed M, Davis Samantha, Tang Alice L, Saunders Lindsay, Brenner J Chadwick, Lin Jiayuh, Fuchs James R, Light Emily, Bradford Carol R, Prince Mark E P, Carey Thomas E
Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI 48109-5616, USA.
Arch Otolaryngol Head Neck Surg. 2011 May;137(5):499-507. doi: 10.1001/archoto.2011.63.
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.
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.
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.
FLLL32 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.
确定一种源自姜黄素的新型小分子抑制剂（FLLL32），其靶向信号转导和转录激活因子（STAT）3，是否会在依赖STAT3的头颈部鳞状细胞癌（HNSCC）细胞中诱导细胞毒性作用，并使肿瘤对顺铂敏感。
基础科学研究。对两种HNSCC细胞系UM-SCC-29和UM-SCC-74B进行顺铂[顺二氨合铂（II）二氯化物]敏感性鉴定。测定STAT3和其他凋亡蛋白的基线表达。确定每种细胞系的FLLL32半数抑制浓度（IC50）剂量，并阐明FLLL32处理对磷酸化STAT3和其他关键蛋白表达的影响。测定顺铂、FLLL32及联合治疗的抗肿瘤疗效。确定顺铂、FLLL32或联合治疗后凋亡细胞的比例。
UM-SCC-29细胞系对顺铂耐药，UM-SCC-74B细胞系对顺铂敏感。两种细胞系均表达STAT3、磷酸化STAT3（pSTAT3）和关键凋亡蛋白。FLLL32下调HNSCC细胞中STAT3的活性形式pSTAT3，并诱导强大的抗肿瘤作用。FLLL32单独或与顺铂联合使用可增加凋亡细胞的比例。FLLL32使顺铂耐药癌细胞敏感，以低4倍剂量的顺铂实现等效的肿瘤杀伤效果。
FLLL32单药治疗可诱导强大的抗肿瘤作用，并使癌细胞对顺铂敏感，在较低剂量的顺铂下可实现等效或更好的抗肿瘤效果。我们的结果表明，FLLL32通过抑制STAT3磷酸化、减少生存信号、增加对凋亡的敏感性以及对顺铂的增敏作用发挥作用。
