Mahanine restores RASSF1A expression by down-regulating DNMT1 and DNMT3B in prostate cancer cells

BACKGROUND: Hypermethylation of the promoter of the tumor suppressor gene RASSF1A silences its expression and has been found to be associated with advanced grade prostatic tumors. The DNA methyltransferase (DNMT) family of enzymes are known to be involved in the epigenetic silencing of gene expression, including RASSF1A, and are often overexpressed in prostate cancer. The present study demonstrates how mahanine, a plant-derived carbazole alkaloid, restores RASSF1A expression by down-regulating specific members of the DNMT family of proteins in prostate cancer cells. RESULTS: Using methylation-specific PCR we establish that mahanine restores the expression of RASSF1A by inducing the demethylation of its promoter in prostate cancer cells. Furthermore, we show that mahanine treatment induces the degradation of DNMT1 and DNMT3B, but not DNMT3A, via the ubiquitin-proteasome pathway; an effect which is rescued in the presence of a proteasome inhibitor, MG132. The inactivation of Akt by wortmannin, a PI3K inhibitor, results in a similar down-regulation in the levels DNMT1 and DNMT3B. Mahanine treatment results in a decline in phospho-Akt levels and a disruption in the interaction of Akt with DNMT1 and DNMT3B. Conversely, the exogenous expression of constitutively active Akt inhibits the ability of mahanine to down-regulate these DNMTs, suggesting that the degradation of DNMT1 and DNMT3B by mahanine occurs via Akt inactivation. CONCLUSIONS: Taken together, we show that mahanine treatment induces the proteasomal degradation of DNMT1 and DNMT3B via the inactivation of Akt, which facilitates the demethylation of the RASSF1A promoter and restores its expression in prostate cancer cells. Therefore, mahanine could be a potential therapeutic agent for advanced prostate cancer in men when RASSF1A expression is silenced

An efficient synthesis of open chain nitroalcohols by regioselective ring opening of cyclic tert-β-nitroalcohols by sodium borohydride: Short synthesis of (±)-tridecan-12-olide and (±)-9-tetradecanolide

325-33

A facile procedure for reduction of azides to amines with aluminium triiodide

128-129It has been demonstrated that a wide variety of aromatic and aliphatic azides can be efficiently reduced to the corresponding amines in good yields with freshly prepared aluminium triiodide. Other functional groups such as ether, ester, nitro and halides remain uneffected.</span

A minor pseudoguaianolide from the aerial parts of <i>Parthenium hysterophorus</i> L.

1187-1189Chemical investigation of the aerial parts of Parthenium hysterophorus L. (Asteraceae) has yielded a new pseudoguaianolide in addition to several previously reported compounds

Synthesis of a new series of 10α-nitrodeoxoartemisinin and their antimalarial activity^†

1125-1128Selective replacement of the C-10 hydroxyl group of dihydroartemisinin by a nitro group gives a hitherto unknown derivative of the potent plant based antimalarial drug artemisinin. The nitrostabilized carbanion at C-10 generated by treating 10α-nitrodeoxoartemisinin with variety of bases and subsequent coupling of this carbanion with several electrophiles led to the synthesis of a new series of artemisinin analogues

A new method for deoxygenation of vicinal diols

Cis and trans vicinal diols have been converted into olefins in one step reaction with chlorotrimethylsilane and sodium iodide

An unusual outcome in the Wittig olefination of artemisinin and its derivatives under microwave irradiation

2622-2624Artemisinin type 1,2,4-trioxanes give ring-contracted derivatives on treatment with triphenylcarbethoxymethylphosphonium chloride and Amberlyst-A21 in THF under microwave irradiation

Organic transformations involving metal-metal salt combination: Dehalogenation of <em>vic</em>-dibromides with Al-NiCl₂. 6H₂O-THF system

528-529The utility of the metal-metal salt combination of Al/NiCh. 6H2O in THF in bringing about dehelogenation of vic-dibromides has been demonstrated with examples

Organic transformations involving metal-metal salt combination: Dehalogenation of vic-dibromides with Al-NiCl₂. 6H₂O-THF system

528-52