Abstract
JAK-2 dysregulation plays an important role as an oncogenic driver, and is thus a promising therapeutic target in hematological malignancies. Ruxolitinib is a pyrrolo[2.3-d]pyrimidine derivative with inhibitory activity against JAK1 and JAK2, moderate activity against TYK2, and minor activity against JAK3. Vorinostat is an HDAC inhibitor that reduces JAK-2 expression, thus affecting JAK-2 mRNA expression and increasing JAK-2 proteasomal deterioration. Here we hypothesized that the combination of ruxolitinib and vorinostat could have synergistic effects against hematological disease. We tested combinations of low doses of ruxolitinib and vorinostat in 12 cell lines, and observed highly synergistic cytotoxic action in six cell lines, which was maintained for up to 120 h in the presence of stromal cells. The sensitivity of the six cell lines may be explained by the broad effects of the drug combination, which can affect various targets. Treatment with the combination of ruxolitinib and vorinostat appeared to induce a possible reversal of the Warburg effect, with associated ROS production, apoptotic events, and growth inhibition. Decreased glucose metabolism may have markedly sensitized the six more susceptible cell lines to combined treatment. Therapeutic inhibition of the JAK/STAT pathway seems to offer substantial anti-tumor benefit, and combined therapy with ruxolitinib and vorinostat may represent a promising novel therapeutic modality for hematological neoplasms.
Highlights
During hematopoietic ontogenesis, cytokines play key roles by initiating the intracellular signals that govern cell fate decisions, such as proliferation and differentiation
Janus kinase (JAK)-2 dysregulation plays an important role as an oncogenic driver, and is a promising therapeutic target in hematological malignancies
JAK-2 dysregulation plays an important role as an oncogenic driver, prompting increasing interest in JAK-2 inhibitors for therapy against hematological malignancies www.impactjournals.com/oncotarget
Summary
Cytokines play key roles by initiating the intracellular signals that govern cell fate decisions, such as proliferation and differentiation. Most cytokine receptors lose intrinsic kinase activity and, often employ Janus kinase (JAK) as a signaling intermediate to facilitate downstream signaling. Receptorrelated non-receptor tyrosine kinases, such as JAK1, JAK2, JAK3, and TYK2, are triggered after cytotoxic receptor activation [1]. JAK activation determines the phosphorylation of STAT transcription factors, including STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. STAT complexes translocate to the nucleus, bind DNA, and begin transcription [2, 3]. Dysregulation of JAK/STAT pathways can cause hematological illnesses and immunodeficiency disorders, and is implicated in the pathogenesis of some solid tumors [4]. Hematologic malignancies exhibit abnormal activation of JAK2 signaling [5]. The JAK2V617F mutation has been identified in different patients with neoplasms, supporting the development of JAK inhibitors to target JAK signaling [6]
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