Kumar Sandeep, Inigo Joseph R, Kumar Rahul, Chaudhary Ajay K, O'Malley Jordan, Balachandar Srimmitha, Wang Jianmin, Attwood Kristopher, Yadav Neelu, Hochwald Steven, Wang Xinjiang, Chandra Dhyan
Department of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
Department of Bioinformatics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Cancer Lett. 2018 Jan 28;413:82-93. doi: 10.1016/j.canlet.2017.10.029. Epub 2017 Oct 26.
Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive disease and current treatment regimens fail to effectively cure PDAC. Development of resistance to current therapy is one of the key reasons for this outcome. Nimbolide (NL), a triterpenoid obtained from Azadirachta indica, exhibits anticancer properties in various cancer including PDAC cells. However, the underlying mechanism of this anticancer agent in PDAC cells remains undefined. We show that NL exerts a higher level of apoptotic cell death compared to the first-line agent gemcitabine for PDAC, as well as other anticancer agents including sorafenib and curcumin. The anticancer efficacy of NL was further evidenced by a reduction in the CD44 as well as cancer stem-like cell (CSC) population, as it causes decreased sphere formation. Mechanistically, the anticancer efficacy of NL associates with reduced mutant p53 as well as increased mitochondrial activity in the form of increased mitochondrial reactive oxygen species and mitochondrial mass. Together, this study highlights the therapeutic potential of NL in mutant p53 expressing pancreatic cancer.
胰腺导管腺癌（PDAC）是一种侵袭性很强的疾病，目前的治疗方案无法有效治愈PDAC。对当前治疗产生耐药性是导致这种结果的关键原因之一。印楝素（NL）是一种从印楝中提取的三萜类化合物，在包括PDAC细胞在内的多种癌症中具有抗癌特性。然而，这种抗癌药物在PDAC细胞中的潜在机制仍不明确。我们发现，与治疗PDAC的一线药物吉西他滨以及包括索拉非尼和姜黄素在内的其他抗癌药物相比，NL能诱导更高水平的凋亡性细胞死亡。NL的抗癌功效还通过CD44以及癌症干细胞样细胞（CSC）数量的减少得到进一步证明，因为它会导致球体形成减少。从机制上讲，NL的抗癌功效与突变型p53的减少以及线粒体活性的增加有关，线粒体活性增加表现为线粒体活性氧和线粒体质量的增加。总之，这项研究突出了NL在表达突变型p53的胰腺癌中的治疗潜力。
