Abstract
We determined whether the myelofibrosis drug ruxolitinib, an inhibitor of Janus kinases 1/2 (JAK1 and JAK2), could interact with the multiple sclerosis drug dimethyl-fumarate (DMF) to kill tumor cells; studies used the in vivo active form of the drug, mono-methyl fumarate (MMF). Ruxolitinib interacted with MMF to kill brain, breast, lung and ovarian cancer cells, and enhanced the lethality of standard of care therapies such as paclitaxel and temozolomide. MMF also interacted with other FDA approved drugs to kill tumor cells including Celebrex® and Gilenya®. The combination of [ruxolitinib + MMF] inactivated ERK1/2, AKT, STAT3 and STAT5; reduced expression of MCL-1, BCL-XL, SOD2 and TRX; increased BIM expression; decreased BAD S112 S136 phosphorylation; and enhanced pro-caspase 3 cleavage. Expression of activated forms of STAT3, MEK1 or AKT each significantly reduced drug combination lethality; prevented BAD S112 S136 dephosphorylation and decreased BIM expression; and preserved TRX, SOD2, MCL-1 and BCL-XL expression. The drug combination increased the levels of reactive oxygen species in cells, and over-expression of TRX or SOD2 prevented drug combination tumor cell killing. Over-expression of BCL-XL or knock down of BAX, BIM, BAD or apoptosis inducing factor (AIF) protected tumor cells. The drug combination increased AIF : HSP70 co-localization in the cytosol but this event did not prevent AIF : eIF3A association in the nucleus.
Highlights
Immune cell activation in general and during rheumatoid arthritis progression requires signaling by Janus kinases (JAK1, JAK2, JAK3)
The present studies were undertaken to determine whether the myelo-proliferative disorder medication and JAK1/2 inhibitor ruxolitinib could be re-purposed as a cancer therapeutic against solid tumors
We discovered that ruxolitinib at clinically relevant free drug concentrations synergized with the multiple sclerosis drug mono-methyl fumarate (MMF) to kill a wide variety of solid tumor cell types, breast www.impactjournals.com/oncotarget and brain tumor cells, including those cells expressing mutated active RAS or ERBB1 proteins, or lacking the tumor suppressor phosphatase and tensin homologue on chromosome ten (PTEN)
Summary
Immune cell activation in general and during rheumatoid arthritis progression requires signaling by Janus kinases (JAK1, JAK2, JAK3). Drug companies, attacking these kinases as drugable targets, have developed several FDA approved agents in the hope of reducing the negative sequelae of arthritis as well as myelo-proliferative disorders: Jakafi and Xeljanz [1,2,3,4]. Mutated active forms of Janus kinases or the actions of mutated activated growth factor receptors through autocrine loops cause constitutive activation of the STAT1 / STAT3 / STAT5 transcription factors that promote the malignant phenotype. Growth factor receptors such as ERBB1 and c-MET have been shown to phosphorylate STAT factors on tyrosine residues thereby promoting dimerization and activation [11, 12]. Cyto-protective genes activated by STAT transcription factors are many and include those coding for: anti-apoptotic genes such as MCL-1, BCL-XL, BCL-2, survivin, HSP90, HSP70; proliferation regulatory genes such as Cyclin D1, Cyclin B, c-Jun, c-Fos; and angiogenesis promoting genes such as HIF1α, and growth factors such as IL-6, FGF, EGF and www.impactjournals.com/oncotarget
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