Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo

摘要: // Laurence Booth 1 , Thomas Albers 3 Jane L. Roberts Mehrad Tavallai Andrew Poklepovic 2 Iryna O. Lebedyeva Paul Dent Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA Medicine, Chemistry Physics, Augusta Summerville Campus, GA 30912, Correspondence to: Dent, email: pdent@vcu.edu Keywords: sorafenib, pazopanib, chaperones, ERBB, PI3K Received: April 25, 2016      Accepted: May 20, Published: 31, 2016 ABSTRACT We have recently demonstrated that multi-kinase inhibitors such as sorafenib pazopanib can suppress the detection chaperones by in situ immuno-fluorescence, which is further enhanced phosphodiesterase 5 inhibitors. Sorafenib inhibited HSP90 ATPase activity with IC50 values ~1.0 μM ~75 nM, respectively. Pazopanib docked silico two possible poses into ATP binding pocket. sildenafil combined to reduce total protein levels HSP1H/p105 c-MYC their co-localization. Sorafenib/pazopanib a [GRP78+HSP27] –dependent fashion (i) profoundly activate an eIF2α/Beclin1 pathway; (ii) inactivate mTOR increase ATG13 phosphorylation, collectively resulting formation toxic autophagosomes. In fresh PDX isolate NSCLC knock down [ERBB1+ERBB3] or use ERBB1/2/4 inhibitor afatinib altered cell morphology, inactivated NFκB, [sorafenib/pazopanib + sildenafil] lethality. Identical data were obtained knocking p110α/β using buparlisib, copanlisib specific p110α BYL719. Afatinib adapted clones resistant buparlisib but more sensitive than control [sorafenib [pazopanib sildenafil]. Lapatinib significantly anti-tumor effect [regorafenib vivo ; BYL719 effects [pazopanib]