Pharmacologic inhibition of STAT5 in acute myeloid leukemia

Abstract

The transcription factor STAT5 is an essential downstream mediator of many tyrosine kinases (TKs), particularly in hematopoietic cancers. STAT5 is activated by FLT3-ITD, which is a constitutively active TK driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 is of significant clinical value. Here, we describe the development and preclinical evaluation of a novel, potent STAT5 SH2 domain inhibitor, AC-4–130, which can efficiently block pathological levels of STAT5 activity in AML. AC-4–130 directly binds to STAT5 and disrupts STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent gene transcription. Notably, AC-4–130 substantially impaired the proliferation and clonogenic growth of human AML cell lines and primary FLT3-ITD+ AML patient cells in vitro and in vivo. Furthermore, AC-4–130 synergistically increased the cytotoxicity of the JAK1/2 inhibitor Ruxolitinib and the p300/pCAF inhibitor Garcinol. Overall, the synergistic effects of AC-4–130 with TK inhibitors (TKIs) as well as emerging treatment strategies provide new therapeutic opportunities for leukemia and potentially other cancers.

Chemical and Biological Aspects of Garcinol and Isogarcinol: Recent Developments

“…The STAT5-SH2 domain inhibitor AC-4-130 showed strongly synergistic effects against acute myeloid leukemia (AML) cells MV4-11 and MOLM-13 in combination with the HAT inhibitor garcinol probably because acetylation of STAT5 by the HATs p300 and PCAF is of importance for the regulation of STAT5 phosphorylation/ dimerisation. [52] Isogarcinol isolated from G. ovalifolia roots exhibited distinct activity against HL-60 promyelocytic leukemia cells (IC 50 = 4 μg/mL) and induced G 2 / M arrest as well as apoptosis via mitochondrial damage in these leukemia cells. [19] While garcinol is only poorly soluble in water, PLGA nanoparticles modified with vitamin E as carriers of garcinol (GAR-NPs) revealed significant growth inhibitory activities against B16-F10 melanoma, HepG2 hepatocellular carcinoma, and KB cervical carcinoma cells.…”

“…Tumor cell growth inhibition [gallbladder carcinoma (garcinol), neuroblastoma (garcinol), melanoma (GAR‐NPs), hepatoma (GAR‐NPs), leukemia (isogarcinol)], synergism with STAT5‐SH2 domain inhibitor AC‐4‐130 (leukemia, garcinol), induction of apoptosis and G2/M arrest (leukemia, isogarcinol), induction of autophagy (osteosarcoma, garcinol)…”

“…Suppression MMP2 and MMP9 (gallbladder carcinoma) (garcinol), synergism with STAT5 inhibition via HAT inhibition (leukemia, garcinol), increased TRAIL‐based apoptosis by induction of DR5 and suppression of c‐FLIP (hepatoma, renal cancer, garcinol), LC‐3 shift (osteosarcoma, garcinol)…”

“…Both garcinol and isogarcinol displayed activities against leukemia models. The STAT5‐SH2 domain inhibitor AC‐4‐130 showed strongly synergistic effects against acute myeloid leukemia (AML) cells MV4‐11 and MOLM‐13 in combination with the HAT inhibitor garcinol probably because acetylation of STAT5 by the HATs p300 and PCAF is of importance for the regulation of STAT5 phosphorylation/dimerisation . Isogarcinol isolated from G. ovalifolia roots exhibited distinct activity against HL‐60 promyelocytic leukemia cells (IC 50 =4 μg/mL) and induced G 2 /M arrest as well as apoptosis via mitochondrial damage in these leukemia cells .…”

“…Tumor cell growth inhibition [gallbladder carcinoma (garcinol), [50] neuroblastoma (garcinol), [51] melanoma (GAR-NPs), [53] hepatoma (GAR-NPs), [53] leukemia (isogarcinol)], [19] synergism with STAT5-SH2 domain inhibitor AC-4-130 (leukemia, garcinol), [52] induction of apoptosis and G2/M arrest (leukemia, isogarcinol), [19] induction of autophagy (osteosarcoma, garcinol) [56] Suppression MMP2 and MMP9 (gallbladder carcinoma) (garcinol), [50] synergism with STAT5 inhibition via HAT inhibition (leukemia, garcinol), [52] increased TRAIL-based apoptosis by induction of DR5 and suppression of c-FLIP (hepatoma, renal cancer, garcinol), [54] LC-3 shift (osteosarcoma, garcinol) [56] Moderate accumulation of garcinol nanoparticles in tumors of B16-F10 tumor bearing mice (GAR-NPs) [53] for this promising drug combination at low doses (1 mg/ kg garcinol orally three times per week + 5 mg/ kg taxol i. p. once per week) attributable to the downregulation of caspase-3/iPLA 2 and NF-κB/Twist1 signaling. [36] The chloroform extract of G. morella rich in bioactive garcinol exhibited distinct growth inhibitory effects against three breast cancer cell lines (MCF-7, MDA-MB-231, SKBR3).…”