Abstract 2583: Effects of garlic compound diallyl trisulfide on head and neck cancer cells and cancer stem cells in vitro and in vivo

Sivapar V Mathan, Su-Hyeong Kim, Shivendra V. Singh, R. Singh
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引用次数: 0

Abstract

Head and neck cancer (HNC) is the seventh most prevalent cancer worldwide. The five-year survival rate is less than fifty percent despite significant advances in therapeutic approaches. Early diagnosis and treatment can help in prevention and disease management. Studies have reported that dietary intake of Allium vegetables or processed garlic that contains diallyl trisulfide (DATS) lowered the risk of various cancers. However, it has not been investigated for its efficacy and molecular mechanisms against HNC. Herein, we investigated the effect of DATS on HNC UMSCC-22A, UMSCC-22B, and Cal33 cells in vitro. DATS treatment significantly reduced the cell viability of HNC cells. DATS induced significant G2/M phase cell cycle arrest, which resulted in the accumulation of cyclin B1 and induced levels of p21. DATS-induced M phase arrest was attenuated by N-acetyl cysteine (NAC) treatment, which suggested that DATS mediates growth-suppressive effects by reactive oxygen species (ROS) generation. DATS treatment induced mitochondrial dysfunction. DATS induced ROS production led to apoptosis, which was attenuated by NAC treatment. DATS increased proapoptotic protein cleaved caspase-3, cleaved PARP, and Bax/Bcl2 ratio and decreased the levels of antiapoptotic protein XIAP. DATS induced ROS mediated DNA damage which was attenuated by NAC treatment. Further, DATS mediated increase in level of cleaved PARP, accumulation of Cyclin B1 and decrease in XIAP was attenuated by NAC treatment. DATS (1-10 μM) treatment resulted in inhibition of self renewal of HNC cancer stem cells (HNC CSCs) sphere formation. DATS reduced aldehyde dehydrogenase 1 (ALDH1) activity and CD133high/CD44high HNC CSC fraction. DATS-treated SCID mice tumor xenograft also revealed it9s in vivo efficacy on HNC CSCs. Further, DATS treatment reduced the tumor weight, volume and reduced the levels of Ki67 cell proliferation marker in UMSCC22B head and neck cancer CD1 nude mice tumor xenograft. DATS treatment decreased tumor incidence and inhibited tumor promotion and progression in twenty two week C57BL6 4-Nitroquinoline 1-oxide (4-NQO)-induced mouse oral carcinogenesis model. DATS treatment reduced the cell proliferation marker Ki67 and increased TUNEL positive apoptotic cells in treatment groups compared to control group. Collectively, DATS inhibited cell proliferation, induced cell cycle arrest, and cell death via apoptosis involving DNA damage, mitochondrial dysfunction, and ROS generation. DATS treatment also reduced the HNC CSC fraction, sphere formation and ALDH1 activity. More importantly, DATS inhibited cancer incidence and progression in 4-NQO oral carcinogenesis study. Further, DATS inhibited HNC tumor growth and HNC CSC fraction in vivo. Thus, DATS could be a potential chemopreventive and chemotherapeutic agent against head and neck cancer. Citation Format: Sivapar V. Mathan, Su-Hyeong Kim, Shivendra V. Singh, Rana P. Singh. Effects of garlic compound diallyl trisulfide on head and neck cancer cells and cancer stem cells in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2583.
2583:大蒜化合物二烯丙基三硫醚对头颈部肿瘤细胞和肿瘤干细胞的体内外作用
头颈癌(HNC)是全球第七大最常见的癌症。尽管治疗方法取得了重大进展,但5年生存率仍不到50%。早期诊断和治疗有助于预防和控制疾病。研究报告说,饮食中摄入含有二烯丙基三硫醚(DATS)的葱类蔬菜或加工过的大蒜可以降低患各种癌症的风险。然而,对其抗HNC的疗效和分子机制尚未进行研究。我们在体外研究了DATS对HNC UMSCC-22A、UMSCC-22B和Cal33细胞的影响。DATS处理显著降低HNC细胞活力。DATS诱导显著的G2/M期细胞周期阻滞,导致细胞周期蛋白B1的积累和p21的诱导水平。n -乙酰半胱氨酸(NAC)处理可减轻DATS诱导的M相阻滞,这表明DATS通过活性氧(ROS)的产生介导了生长抑制作用。DATS治疗诱导线粒体功能障碍。DATS诱导的ROS产生导致细胞凋亡,NAC处理可减轻细胞凋亡。DATS增加促凋亡蛋白裂解caspase-3、裂解PARP和Bax/Bcl2比值,降低抗凋亡蛋白XIAP水平。DATS诱导ROS介导的DNA损伤,NAC处理可减轻这种损伤。此外,NAC处理减弱了DATS介导的裂解PARP水平升高、Cyclin B1积累和XIAP降低。DATS (1-10 μM)处理可抑制HNC癌干细胞(HNC CSCs)的球体形成。DATS降低醛脱氢酶1 (ALDH1)活性和cd133高/ cd44高HNC CSC组分。dats处理的SCID小鼠肿瘤异种移植物也显示出其对HNC CSCs的体内疗效。此外,DATS治疗降低了UMSCC22B头颈癌CD1裸鼠肿瘤异种移植瘤的肿瘤重量、体积和Ki67细胞增殖标志物水平。在C57BL6 - 4-硝基喹啉1-氧化物(4-NQO)诱导的小鼠口腔癌模型中,DATS治疗可降低肿瘤发生率,抑制肿瘤的促进和进展。与对照组相比,DATS处理降低了细胞增殖标志物Ki67,增加了TUNEL阳性凋亡细胞。总的来说,DATS抑制细胞增殖,诱导细胞周期阻滞,并通过涉及DNA损伤、线粒体功能障碍和ROS生成的凋亡导致细胞死亡。DATS处理还降低了HNC CSC分数、球形成和ALDH1活性。更重要的是,在4-NQO口腔癌研究中,DATS抑制了癌症的发生和进展。此外,DATS在体内抑制HNC肿瘤生长和HNC CSC分数。因此,DATS可能是一种潜在的头颈部癌症的化学预防和化学治疗药物。引文格式:Sivapar V. Mathan, Su-Hyeong Kim, Shivendra V. Singh, Rana P. Singh。大蒜化合物二烯丙基三硫醚对头颈部癌细胞及肿瘤干细胞的体内外作用[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要nr 2583。
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