Novel HSP90-PI3K Dual Inhibitor Suppresses Melanoma Cell Proliferation by Interfering with HSP90-EGFR Interaction and Downstream Signaling Pathways

International Journal of Molecular Sciences
Qian ZhaoWei Huang

Abstract

Melanoma is the deadliest form of skin cancer, and its incidence has continuously increased over the past 20 years. Therefore, the discovery of a novel targeted therapeutic strategy for melanoma is urgently needed. In our study, MTT-based cell proliferation assay, cell cycle, and apoptosis assays through flow cytometry, protein immunoblotting, protein immunoprecipitation, designing of melanoma xenograft models, and immunohistochemical/immunofluorescent assays were carried out to determine the detailed molecular mechanisms of a novel HSP90-PI3K dual inhibitor. Our compound, named DHP1808, was found to suppress A375 cell proliferation through apoptosis induction by activating the Fas/FasL signaling pathway; it also induced cell-cycle arrest and inhibited the cell migration and invasion of A375 cells by interfering with Hsp90-EGFR interactions and downstream signaling pathways. Our results indicate that DHP1808 could be a promising lead compound for the Hsp90/PI3K dual inhibitor.

References

Jul 18, 2002·Nature Reviews. Drug Discovery·Renaud CapdevilleAlex Matter
May 16, 2006·Cancer Cell·Qi-Wen FanWilliam A Weiss
May 25, 2006·British Journal of Cancer·E WeisbergJ D Griffin
May 14, 2008·Current Cancer Drug Targets·Amancio CarneroJuan F M Leal
Sep 6, 2008·Nature·UNKNOWN Cancer Genome Atlas Research Network
Jan 17, 2009·Nature Reviews. Microbiology·Tessa BergsbakenBrad T Cookson
Mar 23, 2010·Cell·Kate Schroder, Jurg Tschopp
Jul 23, 2011·Genes & Cancer·Maria-Magdalena Georgescu
Mar 21, 2012·Nature Immunology·Vijay A K RathinamKatherine A Fitzgerald
Oct 13, 2012·Nature Reviews. Drug Discovery·Gideon BollagPeter Hirth
Apr 4, 2013·Science Signaling·Jianjiong GaoNikolaus Schultz
Jun 29, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Soon-Duck HaSung Ouk Kim
Aug 1, 2014·Nature·UNKNOWN Cancer Genome Atlas Research Network
Dec 3, 2014·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Liang OuyangGu He
Jan 13, 2015·Current Topics in Medicinal Chemistry·Nageswara Rao DunnaAnuraj Nayarisseri
May 28, 2016·CA: a Cancer Journal for Clinicians·Mary K TrippJeffrey E Gershenwald
Mar 30, 2017·Cancers·Maria Chiara De SantisEmilio Hirsch
Apr 20, 2017·Cancers·Megan CrumbakerAnthony M Joshua
Apr 22, 2017·Nature Reviews. Molecular Cell Biology·Florian H SchopfJohannes Buchner
Nov 15, 2017·Science China. Life Sciences·Xiaoliang Yu, Sudan He
Jul 17, 2018·The International Journal of Biochemistry & Cell Biology·Saheli SamantaJohnson Rajasingh

❮ Previous
Next ❯

Citations

Dec 16, 2020·International Journal of Molecular Sciences·Sang Chul ShinGyochang Keum
Mar 30, 2021·Signal Transduction and Targeted Therapy·Pian YuXiang Chen
Aug 28, 2021·European Journal of Medicinal Chemistry·Osama M SoltanMohamed Abdel-Aziz
Oct 22, 2021·Molecular & Cellular Proteomics : MCP·Marisa SchmittNicolas C Nalpas

❮ Previous
Next ❯

Methods Mentioned

BETA
protein folding
ubiquitination
flow cytometry
co-immunoprecipitation
xenograft
xenografts
electrophoresis
co-IP

Related Concepts

Related Feeds

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

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.