Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo.
We have recently demonstrated that multi-kinase inhibitors such as sorafenib and pazopanib can suppress the detection of chaperones by in situ immuno-fluorescence, which is further enhanced by phosphodiesterase 5 inhibitors. Sorafenib and pazopanib inhibited the HSP90 ATPase activity with IC50 values of ~1.0 μM and ~75 nM, respectively. Pazopanib docked in silico with two possible poses into the HSP90 ATP binding pocket. Pazopanib and sildenafil combined to reduce the total protein levels of HSP1H/p105 and c-MYC and to reduce their co-localization. Sorafenib/pazopanib combined with sildenafil in a [GRP78+HSP27] -dependent fashion to: (i) profoundly activate an eIF2α/Beclin1 pathway; (ii) profoundly inactivate mTOR and increase ATG13 phosphorylation, collectively resulting in the formation of toxic autophagosomes. In a fresh PDX isolate of NSCLC combined knock down of [ERBB1+ERBB3] or use of the ERBB1/2/4 inhibitor afatinib altered cell morphology, enhanced ATG13 phosphorylation, inactivated NFκB, and further enhanced [sorafenib/pazopanib + sildenafil] lethality. Identical data to that with afatinib were obtained knocking down PI3K p110α/β or using buparlisib, copanlisib or the specific p110α inhibitor BYL719. Afatinib adapted NSCLC clones were resistant to buparlisib or copanlisib but were more sensitive than control clones to [sorafenib + sildenafil] or [pazopanib + sildenafil]. Lapatinib significantly enhanced the anti-tumor effect of [regorafenib + sildenafil] in vivo; afatinib and BYL719 enhanced the anti-tumor effects of [sorafenib + sildenafil] and [pazopanib] in vivo, respectively.
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Laurence
L
Booth
Department of Chemistry and Physics, Augusta University, Summerville Campus, Augusta, GA 30912, USA.
Thomas
T
Albers
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Jane L
JL
Roberts
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Mehrad
M
Tavallai
Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
Andrew
A
Poklepovic
Department of Chemistry and Physics, Augusta University, Summerville Campus, Augusta, GA 30912, USA.
Iryna O
IO
Lebedyeva
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Paul
P
Dent
D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy; D001665:Binding Sites; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007191:Indazoles; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D066247:Receptor, ErbB-4 / Q000037:antagonists & inhibitors*; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D066246:ErbB Receptors; D007191:Indazoles; D018832:Molecular Chaperones; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D000068677:Sildenafil Citrate; D013449:Sulfonamides; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C516667:pazopanib; C508053:ERBB2 protein, human; C587689:ERBB4 protein, human
ERBB; PI3K; chaperones; pazopanib; sorafenib