Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a malignant liver tumor with a rising global incidence and poor prognosis, largely due to late-stage diagnosis and limited effective treatment options. Standard chemotherapy regimens, including cisplatin and gemcitabine, often fail because of the development of multidrug resistance (MDR), leaving patients with few alternative therapies. Doxycycline, a tetracycline antibiotic, has demonstrated antitumor effects across various cancers, influencing cancer cell viability, apoptosis, and stemness. Based on these properties, we investigated the potential of doxycycline to overcome gemcitabine resistance in iCCA. Methods: We evaluated the efficacy of doxycycline in two MDR iCCA cell lines, MT-CHC01R1.5 and 82.3, assessing cell cycle perturbation, apoptosis induction, and stem cell compartment impairment. We assessed the in vivo efficacy of combining doxycycline and gemcitabine in mouse xenograft models. Results: Treatment with doxycycline in both cell lines resulted in a significant reduction in cell viability (IC50~15 µg/mL) and induction of apoptosis. Doxycycline also diminished the cancer stem cell population, as indicated by reduced cholangiosphere formation. In vivo studies showed that while neither doxycycline nor gemcitabine alone significantly reduced tumor growth, their combination led to marked decreases in tumor volume and weight at the study endpoint. Additionally, metabolic analysis revealed that doxycycline reduced glucose uptake in tumors, both as a monotherapy and more effectively in combination with gemcitabine. Conclusions: These findings suggest that doxycycline, especially in combination with gemcitabine, can restore chemotherapy sensitivity in MDR iCCA, providing a promising new strategy for improving outcomes in this challenging disease.
背景/目的：肝内胆管癌（iCCA）是一种恶性肝脏肿瘤，其全球发病率不断上升且预后不良，主要原因是诊断时多为晚期且有效治疗手段有限。以顺铂和吉西他滨为代表的标准化疗方案常因多药耐药性（MDR）的产生而失效，导致患者缺乏替代疗法。多西环素作为一种四环素类抗生素，已在多种癌症中显示出抗肿瘤作用，可影响癌细胞活力、凋亡及干性特征。基于这些特性，本研究探讨了多西环素逆转iCCA吉西他滨耐药性的潜力。方法：我们在两种MDR iCCA细胞系（MT-CHC01R1.5和82.3）中评估多西环素的疗效，检测其对细胞周期扰动、细胞凋亡诱导及干细胞群损伤的影响，并通过小鼠异种移植模型评估多西环素联合吉西他滨的体内疗效。结果：多西环素处理可显著降低两种细胞系的细胞活力（IC50约15 µg/mL）并诱导细胞凋亡。通过胆管球形成实验发现，多西环素还能减少癌症干细胞群。体内研究显示，虽然单独使用多西环素或吉西他滨均未显著抑制肿瘤生长，但联合用药在实验终点时使肿瘤体积和重量显著下降。代谢分析进一步表明，多西环素单药治疗可降低肿瘤葡萄糖摄取，与吉西他滨联用效果更显著。结论：这些发现提示多西环素（尤其是与吉西他滨联用）能够恢复MDR iCCA的化疗敏感性，为改善这一难治性疾病的临床预后提供了新策略。
肿瘤(癌症)患者之家