title: Geridonin and paclitaxel act synergistically to inhibit the proliferation of gastric cancer cells through ROS-mediated regulation of the PTEN/PI3K/Akt pathway.
abstract: Paclitaxel, a taxane, is a cytotoxic chemotherapeutic agent that targets microtubules. It has become a front-line therapy for a broad range of malignancies, including lung, breast, gastric, esophageal, and bladder carcinomas. Although paclitaxel can inhibit tumor development and improve survival, poor solubility, myelotoxicity, allergic reactions, and drug resistance have restricted its clinical application. Paclitaxel is frequently combined with other chemotherapeutics to enhance the antitumor effects and reduce side effects. We synthesized geridonin, a derivative of oridonin, and demonstrate that geridonin and paclitaxel act synergistically to inhibit the growth of gastric cancer cells. Importantly, geridonin enhanced the antitumor effects of paclitaxel without increasing toxicity in vivo. Mechanistic analysis revealed that administration of geridonin in combination with paclitaxel up-regulated the tumor suppressor PTEN and inhibited phosphorylation of Akt and MDM2. This led to the accumulation of p53 and induced apoptosis though the mitochondrial pathway. Thus, geridonin in combination with paclitaxel is a new treatment strategy for gastric cancer.
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P.R. China.
authors.forename: Sai-Qi
authors.initials: SQ
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P.R. China.
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P.R. China.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Chang
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P.R. China.
authors.forename: Kai-Rui
authors.initials: KR
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P.R. China.
authors.forename: Jun-Wei
authors.initials: JW
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ke
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P.R. China.
authors.forename: Dong-Xiao
authors.initials: DX
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P.R. China.
authors.forename: Hong-Ge
authors.initials: HG
authors.lastname: Shi
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P.R. China.
authors.forename: Ran
authors.initials: R
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P.R. China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Shi
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P.R. China.
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Ma
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P.R. China.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D045786:Diterpenes, Kaurane; D017382:Reactive Oxygen Species; C000620433:geridonin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017239:Paclitaxel
keywords: PI3K/Akt pathway; gastric cancer; oridonin; paclitaxel resistance; synergism