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

Laurence Booth, Thomas Albers, Jane L. Roberts, Mehrad Tavallai, Andrew Poklepovic, Iryna O. Lebedyeva, Paul Dent

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)40398-40417
Number of pages20
JournalOncotarget
Volume7
Issue number26
DOIs
StatePublished - Jan 1 2016

Fingerprint

Phosphotransferases
Neoplasms
Clone Cells
Phosphorylation
Phosphodiesterase 5 Inhibitors
Sildenafil Citrate
In Vitro Techniques
pazopanib
Poisons
Phosphatidylinositol 3-Kinases
Computer Simulation
Inhibitory Concentration 50
Adenosine Triphosphatases
sorafenib
Adenosine Triphosphate
Fluorescence
BIBW 2992
Proteins

Keywords

  • Chaperones
  • ERBB
  • PI3K
  • Pazopanib
  • Sorafenib

ASJC Scopus subject areas

  • Oncology

Cite this

Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo. / Booth, Laurence; Albers, Thomas; Roberts, Jane L.; Tavallai, Mehrad; Poklepovic, Andrew; Lebedyeva, Iryna O.; Dent, Paul.

In: Oncotarget, Vol. 7, No. 26, 01.01.2016, p. 40398-40417.

Research output: Contribution to journalArticle

Booth, Laurence ; Albers, Thomas ; Roberts, Jane L. ; Tavallai, Mehrad ; Poklepovic, Andrew ; Lebedyeva, Iryna O. ; Dent, Paul. / Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo. In: Oncotarget. 2016 ; Vol. 7, No. 26. pp. 40398-40417.
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