Department of Surgery and, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Cancer Lett. 2022 Jul 1;537:215591. doi: 10.1016/j.canlet.2022.215591. Epub 2022 Apr 7.
Addition of nab-paclitaxel to gemcitabine offers a survival benefit of only 6 weeks over gemcitabine alone at a cost of increased toxicity in PDAC. The goal of the present study is to evaluate the efficacy of Minnelide, a water-soluble prodrug of triptolide, in combination with the standard of care regimen for chemotherapy with the added advantage of reducing the doses of these drugs to minimize toxicity. Pancreatic cancer cell lines were implanted subcutaneously or orthotopically in athymic nude or C57BL/6J mice. Subsequently, animals were randomized and received saline or minnelide or full dose chemotherapy or low dose chemotherapy or minnelide in combination with low dose chemotherapy. Our results show that a combination of low doses of Minnelide with Gemcitabine + nab-paclitaxel significantly inhibited tumor progression and increased the survival of tumor-bearing mice in comparison with conventional chemotherapy alone. Moreover, combination therapy significantly reduced cancer-related morbidity by decreasing ascites and metastasis and effectively targeted both cancer and the associated stroma. In vitro studies with a combination of low doses of triptolide and paclitaxel significantly decreased the cell viability, increased apoptosis and led to significantly increased M-phase cell cycle arrest in various pancreatic cancer cell lines as compared to either drug alone. Our results show that Minnelide synergizes with conventional chemotherapy leading to a significant reduction in the doses of these toxic drugs, all the while achieving better efficacy in the treatment of PDAC. This combination effectively targeted both the cancer and the associated stromal components of pancreatic cancer.
在 PDAC 中，与单独使用吉西他滨相比，添加 nab-紫杉醇仅能使患者的生存获益延长 6 周，但毒性却增加了。本研究的目的是评估 Minnelide（雷公藤红素的水溶性前药）联合标准治疗方案化疗的疗效，其优势在于降低这些药物的剂量以最大程度地减少毒性。将胰腺癌细胞系皮下或原位植入无胸腺裸鼠或 C57BL/6J 小鼠中。随后，将动物随机分组，接受生理盐水或 Minnelide 或全剂量化疗或低剂量化疗或 Minnelide 联合低剂量化疗。我们的结果表明，与单独使用常规化疗相比，Minnelide 与吉西他滨+nab-紫杉醇的低剂量联合显著抑制了肿瘤的进展，并延长了荷瘤小鼠的生存时间。此外，联合治疗通过减少腹水和转移显著降低了癌症相关发病率，并有效地靶向了癌症和相关的基质。与单独使用紫杉醇相比，低剂量雷公藤红素和紫杉醇联合使用在各种胰腺癌细胞系中显著降低了细胞活力，增加了细胞凋亡，并导致细胞周期 M 期阻滞显著增加。我们的结果表明，Minnelide 与常规化疗协同作用，显著降低了这些毒性药物的剂量，同时在治疗 PDAC 方面取得了更好的疗效。这种联合治疗有效地靶向了胰腺癌的癌症和相关基质成分。
