Methylisoindigo preferentially kills cancer stem cells by interfering cell metabolism via inhibition of LKB1 and activation of AMPK in PDACs

Molecular Oncology
Xinlai ChengStefan Wölfl

Abstract

Pancreatic ductal adenocarcinoma (PDAC) clinically has a very poor prognosis. No small molecule is available to reliably achieve cures. Meisoindigo is chemically related to the natural product indirubin and showed substantial efficiency in clinical chemotherapy for CML in China. However, its effect on PDAC is still unknown. Our results showed strong anti-proliferation effect of meisoindigo on gemcitabine-resistant PDACs. Using a recently established primary PDAC cell line, called Jopaca-1 with a larger CSCs population as model, we observed a reduction of CD133+ and ESA+/CD44+/CD24+ populations upon treatment and concomitantly a decreased expression of CSC-associated genes, and reduced cellular mobility and sphere formation. Investigating basic cellular metabolic responses, we detected lower oxygen consumption and glucose uptake, while intracellular ROS levels increased. This was effectively neutralized by the addition of antioxidants, indicating an essential role of the cellular redox balance. Further analysis on energy metabolism related signaling revealed that meisoindigo inhibited LKB1, but activated AMPK. Both of them were involved in cellular apoptosis. Additional in situ hybridization in tissue sections of PDAC patients r...Continue Reading

References

Mar 12, 2003·Proceedings of the National Academy of Sciences of the United States of America·Muhammad Al-HajjMichael F Clarke
Jan 1, 2004·Chemistry & Biology·Laurent MeijerPaul Greengard
Feb 27, 2004·Proceedings of the National Academy of Sciences of the United States of America·Reuben J ShawLewis C Cantley
Mar 17, 2004·Oncogene·Julian CarreteroMontserrat Sanchez-Cespedes
Sep 2, 2004·Journal of Cancer Research and Clinical Oncology·Gerhard EisenbrandStephan Muehlbeyer
Jun 29, 2005·Leukemia Research·Zhijian XiaoYushu Hao
Nov 30, 2005·Mutagenesis·Hiroyuki Niida, Makoto Nakanishi
Jun 8, 2006·Annual Review of Biochemistry·Dario R AlessiJose R Bayascas
Jun 30, 2006·Annals of Oncology : Official Journal of the European Society for Medical Oncology·E MiniT Mazzei
Feb 7, 2007·Cancer Research·Chenwei LiDiane M Simeone
Jul 14, 2007·European Journal of Medicinal Chemistry·Fadoua BouchikhiPascale Moreau
Sep 26, 2008·Journal of Medicinal Chemistry·Konstantina VougogiannopoulouLaurent Meijer
Oct 29, 2008·Oncogene·K W Yip, J C Reed
Jun 10, 2009·Nature Reviews. Gastroenterology & Hepatology·Han H Wong, Nicholas R Lemoine
Jul 25, 2009·Nature Reviews. Cancer·David B Shackelford, Reuben J Shaw
Sep 29, 2009·Bioorganic & Medicinal Chemistry·Xi Kai WeeMei-Lin Go
Nov 26, 2009·Nature Cell Biology·Ulrich WellnerThomas Brabletz
Apr 30, 2010·The New England Journal of Medicine·Manuel Hidalgo
May 15, 2010·Nature Reviews. Drug Discovery·Simone FuldaGuido Kroemer
May 22, 2010·Bioorganic & Medicinal Chemistry·Xinlai ChengGerhard Eisenbrand
Dec 3, 2010·Nature·Sushma GurumurthyNabeel Bardeesy
Mar 10, 2011·Nature Medicine·Hans Clevers
May 24, 2011·PloS One·Hamed AlborziniaStefan Wölfl
Feb 7, 2012·Cell·Janet E DanceyThomas J Hudson
Mar 23, 2012·Nature Reviews. Molecular Cell Biology·D Grahame HardieSimon A Hawley
Mar 24, 2012·Cancer Cell·Jeffrey A MageeSean J Morrison
Mar 24, 2012·Cancer Cell·Patrick S Ward, Craig B Thompson
Apr 10, 2012·Journal of Immunological Methods·Pavlo HolenyaStefan Wölfl
May 3, 2012·Seminars in Cancer Biology·Aristidis Moustakas, Carl-Henrik Heldin

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Citations

Sep 19, 2019·Anti-inflammatory & Anti-allergy Agents in Medicinal Chemistry·Humaira B NoorMd A T Sagor
Feb 28, 2020·World Journal of Gastrointestinal Oncology·Panagiotis SarantisMichalis V Karamouzis
Mar 15, 2018·International Journal of Molecular Sciences·Mohamed A Abu El MaatyStefan Wölfl
Sep 13, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jana TegethoffXinlai Cheng
Apr 17, 2019·International Journal of Molecular Sciences·Chia-Cheng SuChia-Yang Li
Jan 30, 2021·Natural Product Reports·Chang-Liang YaoDe-An Guo
Aug 6, 2021·Journal of Cellular Physiology·Laia CajaAristidis Moustakas
Jan 8, 2018·ACS Biomaterials Science & Engineering·Jannick TheobaldStefan Wölfl
Sep 2, 2021·JACS Au·Rodrigo A Gama-BrambilaXinlai Cheng

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