Kuete Victor, Saeed Mohamed E M, Kadioglu Onat, Börtzler Jonas, Khalid Hassan, Greten Henry Johannes, Efferth Thomas
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon.
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
Phytomedicine. 2015 Jan 15;22(1):120-7. doi: 10.1016/j.phymed.2014.11.011. Epub 2014 Nov 26.
Wortmannin is a cytotoxic compound derived from the endophytic fungi Fusarium oxysporum, Penicillium wortmannii and Penicillium funiculosum that occurs in many plants, including medicinal herbs. The rationale to develop novel anticancer drugs is the frequent development of tumor resistance to the existing antineoplasic agents. Therefore, it is mandatory to analyze resistance mechanisms of novel drug candidates such as wortmannin as well to bring effective drugs into the clinic that have the potential to bypass or overcome resistance to established drugs and to substantially increase life span of cancer patients. In the present project, we found that P-glycoprotein-overexpressing tumor cells displaying the classical multidrug resistance phenotype toward standard anticancer drugs were not cross-resistant to wortmannin. Furthermore, three point-mutated PIK3CA protein structures revealed similar binding energies to wortmannin than wild-type PIK3CA. This protein is the primary target of wortmannin and part of the PI3K/AKT/mTOR signaling pathway. PIK3CA mutations are known to be associated with worse response to therapy and shortened its activity toward wild-type and mutant PIK3CA with similar efficacy.
渥曼青霉素是一种细胞毒性化合物，源自内生真菌尖孢镰刀菌、渥曼青霉和绳状青霉，存在于许多植物中，包括药草。开发新型抗癌药物的基本原理是肿瘤对现有抗肿瘤药物频繁产生耐药性。因此，必须分析新型候选药物（如渥曼青霉素）的耐药机制，并将有可能绕过或克服对现有药物的耐药性并大幅延长癌症患者寿命的有效药物推向临床。在本项目中，我们发现对标准抗癌药物表现出经典多药耐药表型的过表达P-糖蛋白的肿瘤细胞对渥曼青霉素没有交叉耐药性。此外，三种点突变的PIK3CA蛋白结构显示出与渥曼青霉素的结合能与野生型PIK3CA相似。该蛋白是渥曼青霉素的主要靶点，也是PI3K/AKT/mTOR信号通路的一部分。已知PIK3CA突变与治疗反应较差有关，并且它对野生型和突变型PIK3CA的活性具有相似的疗效且缩短。
