Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea; Department of Convergence Medicine, Asan Medical Center, Seoul 05505, Republic of Korea.
Department of Convergence Medicine, Asan Medical Center, Seoul 05505, Republic of Korea.
Biochem Biophys Res Commun. 2024 Oct 20;730:150369. doi: 10.1016/j.bbrc.2024.150369. Epub 2024 Jul 7.
Gemcitabine is a nucleoside analog widely used as an anticancer agent against several types of cancer. Although gemcitabine sometimes shows excellent effectiveness, cancer cells are often poorly responsive to or resistant to the drug. Recently, specific strains or dysbiosis of the human microbiome were correlated with drug reactivity and resistance acquisition. Therefore, we aimed to identify antibiotic compounds that can modulate the microbiome to enhance the responsiveness to gemcitabine. To achieve this, we confirmed the gemcitabine responsiveness based on public data and conducted drug screening on a set of 250 antibiotics compounds. Subsequently, we performed experiments to investigate whether the selected compounds could enhance the responsiveness to gemcitabine. First, we grouped a total of seven tumor cell lines into resistant and sensitive group based on the IC50 value (1 μM) of gemcitabine obtained from the public data. Second, we performed high-throughput screening with compound treatments, identifying seven compounds from the resistant group and five from the sensitive group based on dose dependency. Finally, the combination of the selected compound, puromycin dihydrochloride, with gemcitabine in gemcitabine-resistant cell lines resulted in extensive cell death and a significant increase in cytotoxic efficacy. Additionally, mRNA levels associated with cell viability and stemness were reduced. Through this study, we screened antibiotics to further improve the efficacy of existing anticancer drugs and overcome resistance. By combining existing anticancer agents and antibiotic substances, we hope to establish various drug combination therapies and ultimately improve cancer treatment efficacy.
吉西他滨是一种广泛用于治疗多种癌症的核苷类似物抗癌药物。尽管吉西他滨有时表现出优异的疗效，但癌细胞对该药物的反应通常较差或产生耐药性。最近，人类微生物组的特定菌株或失调与药物反应性和耐药性的获得有关。因此，我们旨在确定能够调节微生物组以增强对吉西他滨反应性的抗生素化合物。为了实现这一目标，我们根据公共数据确认了吉西他滨的反应性，并对 250 种抗生素化合物进行了药物筛选。随后，我们进行了实验以研究所选化合物是否可以增强对吉西他滨的反应性。首先，我们根据从公共数据中获得的吉西他滨的 IC50 值（1 μM），将总共七种肿瘤细胞系分为耐药组和敏感组。其次，我们进行了高通量筛选化合物处理，根据剂量依赖性从耐药组中确定了七种化合物，从敏感组中确定了五种化合物。最后，将所选化合物盐酸嘌呤霉素与吉西他滨联合应用于吉西他滨耐药细胞系中，导致广泛的细胞死亡和细胞毒性功效显著增加。此外，与细胞活力和干性相关的 mRNA 水平降低。通过这项研究，我们筛选了抗生素以进一步提高现有抗癌药物的疗效并克服耐药性。通过将现有的抗癌药物和抗生素物质相结合，我们希望建立各种药物联合治疗方案，并最终改善癌症治疗效果。
