Ursolic acid promotes apoptosis,autophagy, and chemosensitivity in gemcitabine‐resistant human pancreatic cancer cells

Gemcitabine (GEM) resistance in pancreatic adenocarcinoma mediated by the receptor for advanced glycation end products (RAGE) has been demonstrated. Therefore, investigating the safety and the potential of new auxiliary methods for pancreatic cancer treatment is urgent. Ursolic acid (UA), a natural pentacyclic triterpenoid found in apple peels, rosemary, and thyme, has been reported to have anticancer capacity. This study aimed to reveal the underlying mechanisms of UA in cell death and drug enhancement, especially in GEM‐resistant pancreatic cancer cells. First, GEM‐resistant cells (MIA Paca‐2^GEMR cells) were established by incrementally increasing GEM culture concentrations. UA treatment reduced cell viability through cell cycle arrest and endoplasmic reticulum (ER) stress, resulting in apoptosis and autophagy in a dose‐dependent manner in MIA Paca‐2 and MIA Paca‐2^GEMR cells. High RAGE expression in MIA Paca‐2^GEMR cells was suppressed by UA treatment. Interestingly, knocking down RAGE expression showed similar UA‐induced effects in both cell lines. Remarkably, UA had a drug‐enhancing effect by decreasing cell viability and increasing cell cytotoxicity when combined with GEM treatment. In conclusions, UA triggered ER stress, subsequently regulating apoptosis‐ and autophagy‐related pathways and increasing GEM chemosensitivity in pancreatic cancer cells by inhibiting the expression of RAGE.     

吉西他滨膀胱灌注治疗非肌层浸润性膀胱癌的疗效及血清VEGF的影响

目的 为探究吉西他滨（GEM）膀胱灌注治疗在经尿道膀胱肿瘤电切术（TURBt）后的非肌层浸润性膀胱癌（NMIBC）患者的临床效果以及对血清VEGF的影响。方法 回顾性选取2015年1月~2019年6月在玉溪市人民医院接受TURBt治疗的132例NMIBC患者为研究对象,将患者分为GEM组和吡柔比星组（THP组）,每组均为66例。两组均行TURBt治疗,GEM组术后立即采取GEM膀胱灌注,THP组术后立即采取THP膀胱灌注。通过对比两组术后灌注治疗过程中的不良反应,并随访1年,监测两组术后0.5年、1年的复发情形;分别在灌注前、灌注后0.5年及1年抽取4 mL空腹静脉血,检测血清VEGF的水平。结果 GEM组灌注后0.5年、1年复发率低于THP组,复发时间长于THP组,具有统计学意义（P<0.05）;两组灌注后0.5年、1年血清VEGF水平均低于灌注前,两组灌注后1年血清VEGF水平与灌注后0.5年水平相比,处于一个降低的趋势,但GEM组患者灌注后0.5年、1年血清VEGF均明显低于THP组,下降的趋势更大,差异有统计学意义（P<0.05）。结论 GEM膀胱灌注治疗在NMIBC病人行TURBt后取得的临床效果较好。     

Gemcitabine,paclitaxel, and oxaliplatin (GEMPOX) in the treatment of relapsed/refractory intracranial nongerminomatous germ cell tumors

Intracranial germ cell tumors (GCT) account for less than 5% of all central nervous system tumors in children in Western countries. Approximately 40% are nongerminomatous GCT (NGGCT). Despite correct treatment, 16% to 47% of the patients will relapse. There are no standard approaches in case of recurrence, and treatment in this situation remains a challenge. We report three patients diagnosed with relapsed intracranial NGGCT treated with gemcitabine, paclitaxel, and oxaliplatin, in whom the tumor showed a remarkable response with normalization of tumor markers.     

吉西他滨联合西妥昔单抗对三阴乳腺癌细胞转移相关基质金属蛋白酶-9(MMP-9)活性的影响

目的：探讨吉西他滨联合西妥昔单抗对三阴乳腺癌细胞增殖、迁移、侵袭的影响，并对可能的机制进行初步的探究。方法：将实验分为西妥昔单抗组（150 μg · mL^-1）、吉西他滨联合用药组（西妥昔单抗150 μg · mL^-1，吉西他滨2.8 μg·mL^-1）。通过MTT、Transwell实验检测联合用药对MDA-MB-231细胞增殖、迁移、侵袭能力的影响，Western blotting实验检测合用药对MDA-MB-231细胞MMP-9、TIMP-1、p-IkB、NF-kB-p65表达水平的影响。结果：吉西他滨联合西妥昔单抗作用MDA-MB-231细胞后，其生长被不同程度的抑制，抑制率随吉西他滨浓度的增加而增高（P<0.05）；联合用药组MDA-MB-231细胞迁移、侵袭数目明显减少（P<0.05），同时MMP-9、p-IkB、NF-kB-p65的表达含量降低，TIMP-1表达含量增加。结论：吉西他滨联合西妥昔单抗对三阴乳腺癌细胞增殖、侵袭、迁移具有抑制作用，并明显抑制MMP-9的表达，其机制可能是通过抑制NF-kB通路实现。     

吉西他滨联合顺铂治疗复发转移食管癌的疗效及安全性探讨

目的:探讨吉西他滨联合顺铂治疗复发转移食管癌的疗效及安全性。方法:吉西他滨联合顺铂治疗70例复发或转移的食管鳞癌患者，记录其近期疗效，比较不同近期疗效患者的远期疗效及不良反应。结果:吉西他滨联合顺铂治疗复发转移食管癌患者的客观缓解率为31.43%，能显著延迟治疗有效患者的无进展生存期(progression-free survival，PFS)，药物严重不良反应为血液毒性，但患者能耐受。结论:吉西他滨联合顺铂治疗复发转移食管癌具有一定的近期疗效和远期疗效，且安全可靠，值得临床推广。     

Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches.The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes.Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy.This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.     

Contribution of equilibrative nucleoside transporters 1 and 2 to gemcitabine uptake in pancreatic cancer cells

Hepatic arterial infusion (HAI) chemotherapy is expected to be a more effective and safer method to treat the hepatic metastasis of pancreatic cancer than intravenous (iv) administration because of higher tumor exposure and lower systemic exposure. To clarify the uptake mechanism of nucleoside anticancer drugs, including gemcitabine (GEM), in pancreatic cancer, we investigated the uptakes of radiolabeled uridine (a general substrate of nucleoside transporters) and GEM in pancreatic cancer cell lines MIA‐PaCa2 and As‐PC1. Uridine uptake was inhibited by non‐labeled GEM and also by S‐(4‐nitrobenzyl)‐6‐thioinosine (NBMPR; an inhibitor of equilibrative nucleoside transporters, ENTs) in a concentration‐dependent manner, suggesting that ENTs contribute to uridine uptake in pancreatic cancer cells. As for GEM, saturable uptake was mediated by high‐ and low‐affinity components with K_m values of micromolar and millimolar orders, respectively. Uptake was inhibited in a concentration‐dependent manner by NBMPR and was sodium ion‐independent. Moreover, the concentration dependence of uptake in the presence of 0.1 μM NBMPR showed a single low‐affinity site. These results indicated that the high‐ and low‐affinity sites correspond to hENT1 and hENT2, respectively. The results indicated that at clinically relevant hepatic concentrations of GEM in GEM‐HAI therapy, the metastatic tumor exposure of GEM is predominantly determined by hENT2 under unsaturated conditions, suggesting that hENT2 expression in metastatic tumor would be a candidate biomarker for indicating anticancer therapy with GEM‐HAI.