Biochem Biophys Res Commun. 2020;529(4):1242-1248.
GDC-0980 (apitolisib) treatment with gemcitabine and/or cisplatin synergistically reduces cholangiocarcinoma cell growth by suppressing the PI3K/Akt/mTOR pathway.
제1저자 장동기 · 교신저자 류지곤
소속 (4)
- Department of Internal Medicine, Dongguk University College of Medicine, Dongguk University Ilsan Hospital, Goyang, Republic of Korea.
- School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea. Electronic address: jkryu@snu.ac.kr.
Abstract
Since conventional chemotherapy (gemcitabine and cisplatin) has marginal survival benefit in patients with advanced cholangiocarcinoma (CCA), an effective targeted therapeutic agent is urgently required. Activation of the PI3K/Akt/mTOR signaling pathway is frequently observed in CCA, and thus, PI3K and mTOR are promising therapeutic targets in CCA. Recently a new dual PI3K/mTOR inhibitor GDC-0980 (apitolisib) was introduced. This study was undertaken to examine the activity of apitolisib against CCA cells in vitro and in vivo. Apitolisib treatment strongly reduced Akt and mTOR active phosphorylation levels and attenuated cell growth in two different CCA cell lines (SNU478 and SNU1196). In addition, the cytotoxic activity of apitolisib enhanced the effects of gemcitabine or cisplatin in vitro and increased PARP cleavage. Moreover, we observed these co-treatments significantly reduced colony formation by SNU478 and SNU1196 cells and potently inhibited tumor growth in a mouse xenograft model. The results of the present study show that apitolisib effectively reduces CCA cell growth by suppressing the PI3K/Akt/mTOR pathway. In addition, co-treatments with apitolisib and gemcitabine or cisplatin synergistically enhanced apitolisib activity, which suggests a means of improving the chemotherapeutic sensitivity of CCA.
Copyright © 2020 Elsevier Inc. All rights reserved.
Keywords
ApitolisibChemotherapyCholangiocarcinomaGDC-0980Treatment
Conflict of interest statement
Declaration of competing interest Biochemical and Biophysical Research Communications. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Please note that all Biochemical and Biophysical Research Communications authors are required to report the following potential conflicts of interest with each submission. If applicable to your manuscript, please provide the necessary declaration in the box above. (1) All third-party financial support for the work in the submitted manuscript. (2) All financial relationships with any entities that could be viewed as relevant to the general area of the submitted manuscript. (3) All sources of revenue with relevance to the submitted work who made payments to you, or to your institution on your behalf, in the 36 months prior to submission. (4) Any other interactions with the sponsor of outside of the submitted work should also be reported. (5) Any relevant patents or copyrights (planned, pending, or issued). (6) Any other relationships or affiliations that may be perceived by readers to have influenced, or give the appearance of potentially influencing, what you wrote in the submitted work. As a general guideline, it is usually better to disclose a relationship than not.
그 밖의 정보
- 출판 형태
- Journal Article, Research Support, Non-U.S. Gov't
- 저널
- Biochemical and biophysical research communications · eISSN 1090-2104
- 전자 출판
- 2020-08-08
- MeSH
- Animals · Bridged Bicyclo Compounds, Heterocyclic / pharmacology / therapeutic use · Cell Line, Tumor · Cell Proliferation / drug effects · Cell Survival / drug effects · Cholangiocarcinoma / drug therapy / metabolism / pathology · Cisplatin / pharmacology / therapeutic use · Deoxycytidine / analogs & derivatives / pharmacology / therapeutic use · Drug Synergism · Humans · Male · Mice, Inbred BALB C · Mice, Nude · Phosphatidylinositol 3-Kinases / metabolism · Proto-Oncogene Proteins c-akt / metabolism · Pyrimidines / pharmacology / therapeutic use · Signal Transduction · TOR Serine-Threonine Kinases / metabolism · Xenograft Model Antitumor Assays · Gemcitabine
- Substances
- Bridged Bicyclo Compounds, Heterocyclic · Cisplatin · Deoxycytidine · Phosphatidylinositol 3-Kinases · Proto-Oncogene Proteins c-akt · Pyrimidines · TOR Serine-Threonine Kinases · Gemcitabine · 1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one