Cardiac glycoside sensitized hepatocellular carcinoma cells to TRAIL via ROS generation, p38MAPK, mitochondrial transition, and autophagy mediation

Molecular Carcinogenesis
Mohammad RasheduzzamanSang-Youel Park

Abstract

A major concern in the clinical application of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) in tumors is the development of resistance. Therefore, agents that can potentially restore TRAIL sensitivity are important therapeutic targets for cancer treatment. Herein, we evaluated lanatoside c and digoxin, both of which are widely used cardiac glycosides (CGs), for their ability to sensitize human hepatocellular carcinoma cells (Huh-7 and HepG2) through TRAIL-induced apoptosis. CGs functionalize TRAIL as shown by its effect on intracellular reactive oxygen species (ROS) generation, which damages mitochondrial integrity and thereby confers intrinsic apoptotic caspase cascade during combined treatment. Caspase activation is dependent on ROS as shown by the ability of CGs to generate ROS and the ROS-N-acetylcysteine (NAC) relationship, which inhibits apoptosis during cotreatment by preventing the formation of caspase-8 and -3. Furthermore, CGs triggered p38MAPK phosphorylation and NAC pre-exposure blocked p38MAPK phosphorylation, which demonstrated that p38MAPK was dependent upon ROS generation. Additionally, CGs were found to be potent inducers of AMPK-mediated protective autophagy as pharmacological and genetic au...Continue Reading

References

Nov 15, 2000·American Journal of Physiology. Lung Cellular and Molecular Physiology·V J Thannickal, B L Fanburg
Dec 21, 2002·Molecular Immunology·Christoph Borner
Mar 5, 2004·Biochimica Et Biophysica Acta·Martin R Sprick, Henning Walczak
Nov 24, 2004·Nature Cell Biology·Shigeomi ShimizuYoshihide Tsujimoto
Jan 20, 2005·Molecular and Cellular Biology·Patricia BoyaGuido Kroemer
Jun 30, 2005·Journal of Cell Science·Rosa-Ana González-PoloGuido Kroemer
Mar 7, 2006·Critical Reviews in Clinical Laboratory Sciences·José M EstrelaElena Obrador
Dec 23, 2006·Cell Death and Differentiation·U SivaprasadA Basu
Apr 12, 2007·Critical Reviews in Therapeutic Drug Carrier Systems·Jayant J Khandare, Tamara Minko
Aug 23, 2007·Nature Reviews. Molecular Cell Biology·Daniel J Klionsky
Mar 12, 2008·Molecular Interventions·Robert A NewmanKeith I Block
Nov 21, 2008·Proceedings of the National Academy of Sciences of the United States of America·Huafeng ZhangGregg L Semenza
Feb 6, 2009·World Journal of Gastroenterology : WJG·Isabel Fabregat
Jan 5, 2010·Current Opinion in Cell Biology·Kevin MoreauDavid C Rubinsztein
Feb 11, 2010·Cell·Noboru MizushimaBeth Levine
Jun 10, 2010·Oncogene·F Gonzalvez, A Ashkenazi
Aug 30, 2011·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Maja MisirkicVladimir Trajkovic
Sep 1, 2011·Molecular Cancer Therapeutics·Zhineng J YangFrank A Sinicrope
Dec 13, 2012·Oncology Reports·Nak-Mi SongDongchul Kang
Mar 26, 2013·Oncoimmunology·Laurie MengerLorenzo Galluzzi
Jun 12, 2013·Investigational New Drugs·M SlingerlandH Gelderblom
Oct 1, 2013·Trends in Molecular Medicine·Daniel W Stuckey, Khalid Shah
Feb 28, 2014·Molecular Pharmacology·Andrew ThorburnDaniel L Gustafson
Jun 10, 2014·Frontiers in Oncology·Yoshihiro Suzuki-KarasakiToyoko Ochiai
Jun 21, 2014·Cell Death and Differentiation·J LemkeH Walczak
Apr 18, 2015·Frontiers in Oncology·Rachana Trivedi, Durga Prasad Mishra
Aug 11, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Di WenRam I Mahato
Sep 8, 2015·Pharmacology & Therapeutics·Gustavo P Amarante-Mendes, Thomas S Griffith
Feb 8, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Ramalingam VaikundamoorthyRajaram Rajendran
Mar 5, 2016·Cell Death and Differentiation·D de MiguelL Martinez-Lostao
Apr 8, 2016·Data in Brief·Rubén Gómez-SánchezRosa A González-Polo
Jun 28, 2016·Current Treatment Options in Oncology·Louise C ConnellGhassan K Abou-Alfa
May 26, 2017·Nature Reviews. Cancer·Silvia von KarstedtHenning Walczak
Jul 29, 2017·Nature Reviews. Cancer·Jean M Mulcahy LevyAndrew Thorburn
Apr 20, 2018·Cancer·Angelique V OnoratiRavi K Amaravadi

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

Autophagy & Model Organisms

Autophagy is a cellular process that allows degradation by the lysosome of cytoplasmic components such as proteins or organelles. Here is the latest research on autophagy & model organisms

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis