(−)-Liriopein B Suppresses Breast Cancer Progression via Inhibition of Multiple Kinases

Numerous breast cancer patients who achieve an initial response to HER-targeted therapy rapidly develop resistance within one year, leading to treatment failure. Observations from clinical samples indicate that such resistance correlates with an increase in Src, EGFR, and PI3K/Akt activities and a decrease in PTEN activity. Furthermore, Akt survival signaling activation is also found in tumors treated by toxic chemotherapeutic agents. Because cotreatment with a PI3K inhibitor is a promising strategy to delay acquired resistance by preventing secondary gene activation, we therefore investigated the effects of a newly identified compound, (−)-Liriopein B (LB), on PI3K/Akt signaling activity in breast cancer cells. Our results showed that nontoxic doses of LB are able to inhibit AKT activation in both luminal-like MCF-7 and basal-like MDA-MB-231 breast cancer cells. Low doses of LB also inhibited cell migration, invasion, and cancer-stem cell sphere formation. Suppression of EGF-induced EGFR and ERK1/2 activation by LB might contribute in part to retardation of cancer progression. Furthermore, LB increases sensitivity of MDA-MB-231 cells to gefitinib in vitro, suggesting that EGFR may not be the only target of LB. Finally, a small scale in vitro kinase assay screen demonstrated that LB has a potent inhibitory effect on multiple kinases, including PI3K, Src, EGFR, Tie2, lck, lyn, RTK5, FGFR1, Abl, and Flt. In conclusion, this study demonstrates for the first time that the compound LB improves tumor therapeutic efficacy and suggests LB as a promising candidate for studying new leads in the development of kinase inhibitors

Tenuipyrone, a Novel Skeletal Polyketide from the Entomopathogenic Fungus, <i>Isaria tenuipes</i>, Cultivated in the Presence of Epigenetic Modifiers

The concomitant addition of the histone deacetylase inhibitor and the DNA methyltransferase inhibitor to the culture medium of an entomopathogenic fungus, <i>Isaria tenuipes</i>, greatly enhanced its secondary metabolite production and led to the isolation of tenuipyrone (<b>1</b>), a novel polyketide with an unprecedented tetracyclic ring system bearing a spiroketal structural component, along with two known C₁₀-polyketides, cephalosporolide B (<b>2</b>), which is a plausible biosynthetic precursor of <b>1</b>, and cephalosporolide F (<b>3</b>)

Withanolides induce degradation of Hsp90 client proteins and induction of Hsp70 in MDA-MB-231 cells.

<p>(A) Cells were treated with the indicated concentrations of various withanolide compounds for 12 h. After treatment, cells were harvested and analyzed for the Hsp90 client proteins (Raf-1, CDK4, and Akt), a non-Hsp90 client protein p85, and Hsp70 by Western blot. (B) Concentration-dependent effect of WA, HW, and AA on the Hsp90 client proteins and Hsp70. GM (10 µM) was used as a positive control. (C, D) Knockdown of Hsp70 enhances the pro-apoptotic effect of the withanolides. MDA-MB-231 cells were transfected with shRNA plasmid against Hsp70 or control plasmid for 48 h. The knockdown efficiency of shRNA for Hsp70 was confirmed by Western blot (C). The transfected cells were treated with WA (2 µM), HW (5 µM), or AA (20 µM) for another 48 h for determining apoptosis (D).</p

Withanolides induce apoptosis in MDA-MB-231 cells.

<p>(A) Cells were treated with the indicated concentrations of WA, HW, AA, and geldanamycin (GM) for 48 h. After treatment, cells were harvested and analyzed for PARP and caspase-3 by Western blot. (B) Cells were treated with WA (5 µM), HW (20 µM), AA (20 µM), or GM (10 µM) for 48 h. Harvested cells were then stained with annexin V-FITC and PI and analyzed by flow cytometry. Percentages of annexin V-positive cells were calculated by combining annexin V⁺/PI⁻ (lower right quadrants) and annexin V⁺/PI⁺ (upper right quadrants) cells. Results are presented as means ± S.E.M. (n = 3).</p

Effects of ursolic acid (UA) on elastase release in N-formyl-methionyl-leucyl-phenylalanine (FMLP) in the pre-priming with cytochalasin B (FMLP/CB)-activated human neutrophils.

<p>Data are shown as mean±SEM (n = 4). *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001 compared to the control.</p

Copper-Catalyzed Oxidative Coupling of Formamides with Salicylaldehydes: Synthesis of Carbamates in the Presence of a Sensitive Aldehyde Group

A diverse library of novel carbamates was synthesized utilizing copper-catalyzed oxidative C–O coupling of formamides and salicylaldehydes. Sensitive aldehyde groups remained intact in the presence of an oxidant and a transition-metal salt. Salicylaldehydes bearing electron-donating, electron-withdrawing, and halogen groups as well as 1-hydroxy-2-naphthaldehydes provided the desired carbamates in good to excellent yields

Synthetic procedure of phenanthrene derivatives.

<p>Reagents and conditions: (i) DDQ, benzene, RT. (ii) TFA, ether, RT. (iii) Me₂SO₄, K₂CO₃, acetone, reflux. (iv) P₄-<i>t</i>Bu, benzene, 140°C. (v) AgO, 6 N HNO₃, acetone, 60°C.</p

Cytotoxicity data of synthesized phenanthrenes.

a<p>Doxorubicin (Doxo) was used as the positive control.</p

Iron-Catalyzed Oxidative Direct α‑C–H Bond Functionalization of Cyclic Ethers: Selective C–O Bond Formation in the Presence of a Labile Aldehyde Group

Iron catalyzed oxidative coupling of salicylaldehydes with cyclic ethers proceeded through the direct α-C–H functionalization of ethers, forming the corresponding acetals in moderate to excellent yields. This is the first example of iron catalyzed selective C–O bond formation in the presence of a sensitive aldehyde moiety

Effect of withanolide on the IKK/NF-κB pathway.

<p>(A) Withanolides induce IKK degradation and inhibit NF-κB activation. MDA-MB-231 cells were treated with WA (5 µM), HW (20 µM), AA (20 µM), PH (20 µM) or GM (10 µM) for 12 h. After treatment, cells were harvested and analyzed for the proteins involved in the NF-κB pathway by Western blotting. (B) Withanolides decrease anti-apoptotic proteins that are regulated by NF-κB. Cells were treated with withanolides for 48 h. After treatment, cells were harvested and analyzed for Bcl-2, Bcl-xL, and c-FLIP by Western blotting. (C) NAC prevents IKK degradation and NF-κB inhibition by WA. Cells were treated with WA (5 µM) or GM (10 µM) in the absence or presence of NAC (2.5 mM) for 12 h. After treatment, cells were harvested and subjected to Western blotting.</p