Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China; International Association for Diagnosis and Treatment of Cancer, Shenzhen, Guangdong, 518055, China; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Department of Oncology, Chongqing Hyheia Hospital, Chongqing, 4001331, China.
Environ Res. 2024 Jan 1;240(Pt 2):117443. doi: 10.1016/j.envres.2023.117443. Epub 2023 Oct 18.
A high number of cancer patients around the world rely on gemcitabine (GEM) for chemotherapy. During local metastasis of cancers, surgery is beneficial for therapy, but dissemination in distant organs leads to using chemotherapy alone or in combination with surgery to prevent cancer recurrence. Therapy failure can be observed as a result of GEM resistance, threatening life of pancreatic cancer (PC) patients. The mortality and morbidity of PC in contrast to other tumors are increasing. GEM chemotherapy is widely utilized for PC suppression, but resistance has encountered its therapeutic impacts. The purpose of current review is to bring a broad concept about role of biological mechanisms and pathways in the development of GEM resistance in PC and then, therapeutic strategies based on using drugs or nanostructures for overcoming chemoresistance. Dysregulation of the epigenetic factors especially non-coding RNA transcripts can cause development of GEM resistance in PC and miRNA transfection or using genetic tools such as siRNA for modulating expression level of these factors for changing GEM resistance are suggested. The overexpression of anti-apoptotic proteins and survival genes can contribute to GEM resistance in PC. Moreover, supportive autophagy inhibits apoptosis and stimulates GEM resistance in PC cells. Increase in metabolism, glycolysis induction and epithelial-mesenchymal transition (EMT) stimulation are considered as other factors participating in GEM resistance in PC. Drugs can suppress tumorigenesis in PC and inhibit survival factors and pathways in increasing GEM sensitivity in PC. More importantly, nanoparticles can increase pharmacokinetic profile of GEM and promote its blood circulation and accumulation in cancer site. Nanoparticles mediate delivery of GEM with genes and drugs to suppress tumorigenesis in PC and increase drug sensitivity. The basic research displays significant connection among dysregulated pathways and GEM resistance, but the lack of clinical application is a drawback that can be responded in future.
全世界有大量癌症患者依赖于吉西他滨（GEM）进行化疗。在癌症的局部转移中，手术对治疗有益，但在远处器官的扩散会导致单独使用化疗或联合手术以防止癌症复发。由于 GEM 耐药性的出现，可观察到治疗失败，这威胁到胰腺癌（PC）患者的生命。PC 的死亡率和发病率与其他肿瘤相比正在增加。GEM 化疗广泛用于抑制 PC，但耐药性已对其治疗效果产生影响。目前综述的目的是广泛介绍生物学机制和途径在 PC 中 GEM 耐药性发展中的作用，然后提出基于使用药物或纳米结构来克服化疗耐药性的治疗策略。表观遗传因子（尤其是非编码 RNA 转录物）的失调可能导致 PC 中 GEM 耐药性的发展，并且建议通过 miRNA 转染或使用 siRNA 等遗传工具来调节这些因子的表达水平以改变 GEM 耐药性。抗凋亡蛋白和存活基因的过表达可导致 PC 中 GEM 耐药性的产生。此外，支持性自噬可抑制 PC 细胞中的凋亡并刺激 GEM 耐药性。增加代谢、诱导糖酵解和上皮-间充质转化（EMT）刺激被认为是 PC 中 GEM 耐药性的其他参与因素。药物可以抑制 PC 中的肿瘤发生并抑制生存因子和途径，从而提高 PC 中 GEM 的敏感性。更重要的是，纳米颗粒可以提高 GEM 的药代动力学特征，并促进其在癌症部位的血液循环和积累。纳米颗粒介导 GEM 与基因和药物的递送来抑制 PC 中的肿瘤发生并提高药物敏感性。基础研究显示失调途径与 GEM 耐药性之间存在显著联系，但缺乏临床应用是未来需要解决的一个缺点。
