Yi Yong Weon, Park Na Young, Park Joo-In, Seong Yeon-Sun, Hong Young Bin
Department of Nanobiomedical Science and BK21 PLUS Research Center for Regenerative Medicine, Dankook University Cheonan, Korea.
Department of Translational Biomedical Sciences, Graduate School of Dong-A University Busan 49201, Korea.
Am J Cancer Res. 2021 Jul 15;11(7):3515-3536. eCollection 2021.
Gemcitabine is often recommended as a first-line treatment for patients with metastatic pancreatic cancer. However, gemcitabine resistance is a major challenge in the treatment of pancreatic ductal adenocarcinoma. Our group serendipitously identified the role of doxycycline as a potentiator of gemcitabine efficacy in pancreatic cancer cells. Doxycycline and gemcitabine co-treatment was significantly more cytotoxic to pancreatic cancer cells compared to gemcitabine alone. Interestingly, doxycycline only exerted synergistic effects when coupled with gemcitabine as opposed to other conventional chemotherapeutics including nucleoside analogs. The anti-clonogenic effects of gemcitabine on pancreatic cancer cells were also enhanced by doxycycline. According to cell cycle analyses, doxycycline prolonged gemcitabine-mediated S phase cell cycle arrest. Further, gene expression profiling analyses indicated that a small set of genes involved in cell cycle regulation were uniquely modulated by gemcitabine and doxycycline co-treatment compared to gemcitabine alone. Western blot analyses indicated that several cell cycle-related proteins, including cyclin D1, p21, and DNA damage inducible transcript 4 (DDIT4), were further modulated by doxycycline and gemcitabine co-treatment. Taken together, our findings indicate that doxycycline enhances the effects of gemcitabine on cell cycle progression, thus rendering pancreatic cancer cells more sensitive to gemcitabine. However, additional studies are required to assess the mechanisms of doxycycline and gemcitabine synergism, which might lead to novel treatment options for pancreatic cancer.
吉西他滨常被推荐作为转移性胰腺癌患者的一线治疗药物。然而，吉西他滨耐药是胰腺导管腺癌治疗中的一项重大挑战。我们团队意外发现强力霉素在胰腺癌细胞中可增强吉西他滨的疗效。与单独使用吉西他滨相比，强力霉素与吉西他滨联合治疗对胰腺癌细胞的细胞毒性显著更强。有趣的是，与包括核苷类似物在内的其他传统化疗药物不同，强力霉素仅在与吉西他滨联合使用时才发挥协同作用。强力霉素还增强了吉西他滨对胰腺癌细胞的抗克隆形成作用。根据细胞周期分析，强力霉素延长了吉西他滨介导的S期细胞周期阻滞。此外，基因表达谱分析表明，与单独使用吉西他滨相比，一小部分参与细胞周期调控的基因在吉西他滨与强力霉素联合治疗时受到独特调节。蛋白质印迹分析表明，包括细胞周期蛋白D1、p21和DNA损伤诱导转录物4（DDIT4）在内的几种细胞周期相关蛋白在强力霉素与吉西他滨联合治疗时受到进一步调节。综上所述，我们的研究结果表明，强力霉素增强了吉西他滨对细胞周期进程的影响，从而使胰腺癌细胞对吉西他滨更敏感。然而，需要进一步研究来评估强力霉素与吉西他滨协同作用的机制，这可能会为胰腺癌带来新的治疗选择。
