d -3-Deoxy-dioctanoylphosphatidylinositol induces cytotoxicity in human MCF-7 breast cancer cells via a mechanism that involves downregulation of the D-type cyclin-retinoblastoma pathway

Abstract

Phosphatidylinositol analogs (PIAs) were originally designed to bind competitively to the Akt PH domain and prevent membrane translocation and activation. D-3-deoxydioctanoylphosphatidylinositol (D-3-deoxy-diC8PI), but not compounds with altered inositol stereochemistry (e.g., L-3-deoxy-diC8PI and L-3,5-dideoxy-diC8PI), is cytotoxic. However, high resolution NMR field cycling relaxometry shows that both cytotoxic and non-toxic PIAs bind to the Akt1 PH domain at the site occupied by the cytotoxic alkylphospholipid perifosine. This suggests another mechanism for cytotoxicity must account for the difference in efficacy of the synthetic short-chain PIAs. In MCF-7 breast cancer cells, with little constitutively active Akt, D-3-deoxy-diC8PI (but not L-compounds) decreases viability concomitant with increased cleavage of PARP and caspase 9, indicative of apoptosis. D-3-deoxy-diC8PI also induces a decrease in endogenous levels of cyclins D1 and D3 and blocks downstream retinoblastoma protein phosphorylation. siRNA-mediated depletion of cyclin D1, but not cyclin D3, reduces MCF-7 cell proliferation. Thus, growth arrest and cytotoxicity induced by the soluble D-3-deoxy-diC8PI occur by a mechanism that involves downregulation of the D-type cyclin-pRb pathway independent of its interaction with Akt. This ability to downregulate D-type cyclins contributes, at least in part, to the anti-proliferative activity of D-3-deoxy-diC8PI and may be a common feature of other cytotoxic phospholipids.

Anti-Inflammatory (M2) Response Is Induced by a sp2-Iminosugar Glycolipid Sulfoxide in Diabetic Retinopathy

“…As demonstrated in recent studies, HO-1 and IL10 are able to induce their anti-inflammatory effects in a reciprocal manner ( 29 ). Also, it is important to note that this reciprocal induction is dependent on p38α MAPK activation ( 30 , 31 ). We previously demonstrated that DSO 2 -ONJ induced p38α MAPK auto-phosphorylation upon binding to the allosteric lipid binding site, a conformational structural change.…”

The sp 2 -iminosugar glycolipid 1-dodecylsulfonyl-5 N ,6 O -oxomethylidenenojirimycin (DSO 2 -ONJ) as selective anti-inflammatory agent by modulation of hemeoxygenase-1 in Bv.2 microglial cells and retinal explants

“…It is important to note that HO-1 and IL-10 can perpetuate their anti-inflammatory effects in a reciprocal manner [49]. Moreover, both HO-1-induced IL-10 production and IL-10induced HO-1 activation are dependent on p38α MAPK activation [50][51][52][53]. In this regard our results strongly suggest that DSO 2 -ONJ selectively up-regulates the synthesis of the anti-inflammatory cytokine IL-10 in a manner likely dependent on HO-1 due to both the canonical and non-canonical p38α MAPK activation [58].…”