Dihydroxypentamethoxyflavone Down-Regulates Constitutive and Inducible Signal Transducers and Activators of Transcription-3 through the Induction of Tyrosine Phosphatase SHP-1

Abstract

Because constitutive activation of signal transducers and activators of transcription-3 (STAT3) has been linked with cellular transformation, survival, proliferation, chemoresistance, and angiogenesis of various tumor cells, agents that can suppress STAT3 activation have potential as cancer therapeutics. In the present report, we identified a flavone from the leaves of a Thai plant, Gardenia obtusifolia, 5,6,7,8,, that has the ability to inhibit STAT3 activation. PMF inhibited both constitutive and interleukin-6-inducible STAT3 activation in multiple myeloma (MM) cells, as indicated by suppression of STAT3 phosphorylation, nuclear translocation, DNA binding, and STAT3-regulated gene expression. The inhibition of STAT3 by PMF was reversible. We found that the activation of various kinases including Janus-like kinase (JAK)-1, JAK-2, c-Src, extracellular signal-regulated kinases 1 and 2, AKT, and epidermal growth factor receptor, implicated in STAT3 activation, were inhibited by the flavone. It is noteworthy that pervanadate suppressed the ability of PMF to inhibit the phosphorylation of STAT3, suggesting that protein tyrosine phosphatase was involved. PMF induced the expression of SHP-1 and was linked to the dephosphorylation of STAT3, because its deletion by small interfering RNA abolished the PMF-induced constitutive and inducible STAT3 inhibition. STAT3 inhibition led to the suppression of proteins involved in proliferation (cyclin D1 and c-myc), survival (survivin, Mcl-1, Bcl-xL, Bcl-2, and cIAP-2), and angiogenesis (vascular endothelial growth factor). Finally, PMF inhibited proliferation and induced apoptosis of MM cells. PMF also significantly potentiated the apoptotic effects of Velcade and thalidomide in MM cells. Overall, these results suggest that PMF is a novel blocker of STAT3 activation and thus may have potential in suppression of tumor cell proliferation and reversal of chemoresistance in MM cells.

Antivascular and anti-parasite activities of natural and hemisynthetic flavonoids from New Caledonian Gardenia species (Rubiaceae)

“…The IC 50 values of these compounds were then determined in the low micromolar concentration range and therefore presented significant inhibitory activity on the tubulin polymerization. Santin (8) showed the most promising profile (5.7 mM), while 1, 2 and 3 exhibited a similar activity with IC 50 of 19.3, 17.8 and 21.4 mM, Scheme 1. Flavonoids from G. urvillei and G. oudiepe and modified analogues.…”

“…The good activity of 5,7-dihydroxy-3,3 0 ,4 0 ,6-tetramethoxyflavone (1) and santin (8) was also presented by centaureidin (3 0 ,5,7-trihydroxy-3,4 0 ,6-trimethoxy-flavone) [26e28] the only 3-methoxy-flavone bearing this kind of substitution on the A ring evaluated for ITP. The structural differences are in 3 0 on the B ring: the lack of a hydroxyl group for 1 and a methoxyl group instead of a hydroxyl one for 8.…”

“…Chromatographic separations on silica gel permitted the isolation of the following flavonoids: 5,7-dihydroxy-3,3 0 ,4 0 ,6-tetramethoxyflavone (1) and 3 0 ,5,7-trihydroxy-3,4 0 ,5 0 ,6-tetramethoxyflavone (2) from G. oudiepe; 5,7-dihydroxy-3,3 0 ,4 0 ,5 0 ,6-pentamethoxyflavone (3), 4 0 ,5,7-trihydroxy-3,6,8-trimethoxyflavone (6), 4 0 ,5,7-trihydroxy-3,6-dimethoxyflavone (7), santin (5,7-dihydroxy-3,4 0 ,6-trimethoxyflavone) (8), and 3-methoxy-kaempferol (kaempferol-3-monomethylether) (12), from G. urvillei (Scheme 1). Some of these natural products were rarely mentioned in the literature, sometimes without or with incomplete NMR data (See Supporting Information).…”

Abnormal repression of SHP-1, SHP-2 and SOCS-1 transcription sustains the activation of the JAK/STAT3 pathway and the progression of the disease in multiple myeloma

“…Hence, the level of SHP gene expression could be a predictive factor of a favorable response to induction therapy. Another hypothesis could be that thalidomide and\or dexamethasone may act similarly to other molecules by inducing the transcription of SHP-1/2 in the malignant plasma cells [46–49]. Subsequently, this could efficiently inhibit the JAK/STAT pathway and induce apoptosis of tumor cells.…”

IgE-dependent signaling as a therapeutic target for allergies

“…This particular process is exploited in a therapeutic approach discussed below, but it demonstrates the potential power of targeting enzymes involved in terminating the ongoing reaction. Recent studies of the drug AKBA (acetyl-11-keto-β-boswellic acid), an anti-inflammatory in clinical use, suggest that it acts to suppress STAT3 phosphorylation by up-regulating the expression of SHP-1 [45]. Similar approaches might be applicable in mast cells/basophils.…”