YQ36: A Novel Bisindolylmaleimide Analogue Induces KB/VCR Cell Death

Overexpression of multidrug resistance proteins P-glycoprotein (P-gp, MDR1) causes resistance of the tumor cells against a variety of chemotherapeutic agents. 3-(1-methyl-1H-indol-3-yl)-1-phenyl-4-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-1H-pyrrole-2,5-dione (YQ36) is a novel analogue of bisindolylmaleimide, which has been reported to overcome multidrug resistance. Here, we dedicated to investigate the anticancer activity of YQ36 on KB/VCR cells. The results revealed that YQ36 exhibited great antiproliferative activity on three parental cell lines and MDR1 overexpressed cell lines. Moreover, the hypersensitivity of YQ36 was confirmed on the base of great apoptosis induction and unaltered intracellular drug accumulation in KB/VCR cells. Further results suggested that YQ36 could not be considered as a substrate of P-gp, which contributed to its successfully escaping from the efflux mediated by P-gp. Interestingly, we observed that YQ36 could accumulate in nucleus and induce DNA damage. YQ36 could also induce the activation of caspase-3, imposing effects on the mitochondrial function. Collectively, our data demonstrated that YQ36 exhibited potent activities against MDR cells, inducing DNA damage and triggering subsequent apoptosis via mitochondrial pathway

Total synthesis of amphidinolide X and its 12Z-isomer by formation of the C12-C13 trisubstituted double bond via ring-closing metathesis

Amphidinolide X, a 16-membered cytotoxic macrodiolide, and its 12Z-isomer have been synthesized via ring-closing metathesis (RCM) for assembling the C12-C13 trisubstituted double bond. A 29:71 E/Z mixture was obtained from the seco substrate appended with a bulky C8-ODPS group in 50-65\% combined yields by using 20 mol\% of the second-generation Grubbs initiator and the corresponding indenylidene ruthenium Complex, Amphidinolide X and 12Z-isomer exhibit similar cytotoxicity (IC50: 7.6-13.9 mu g/mL) against A549, KB, and HL60 cell lines

Nutlin-3 inhibits epithelial-mesenchymal transition by interfering with canonical transforming growth factor-beta 1-Smad-Snail/Slug axis

Enormous efforts have been made to explore small molecules that interfere with the TGF-beta signaling pathway, so as to inhibit EMT and the cancer metastasis, but few agents have been identified. In this study, we demonstrated that Nutlin-3 could abolish the down-regulation of E-cadherin induced by TGF-beta 1 in p53-deficient cancer cells. Further studies revealed that Nutlin-3 prohibited EMT by blocking the phosphorylation of Smad2/3, resulting in the decreased transcription of Snail/Slug. In addition, Nutlin-3 suppressed the motility of cancer cells, and potentiated the anti-proliferative activity of gefitinib and lapatinib. Collectively, Nutlin-3 could inhibit EMT and enhance the anti-cancer activity of EGFR inhibitors by interfering with the canonical TGF-beta 1-Smad-Snail/Slug axis, in a p53-independent manner

A Modified Chinese Herbal Decoction (Kai-Xin-San) Promotes NGF-Induced Neuronal Differentiation in PC12 Cells via Up-Regulating Trk A Signaling

Kai-Xin-San (KXS), a Chinese herbal decoction, has been applied to medical care of depression for thousands of years. It is composed of two functional paired-herbs: Ginseng Radix et Rhizoma (GR)-Polygalae Radix (PR) and Acori Tatarinowii Rhizoma (ATR)-Poria (PO). The compatibility of the paired-herbs has been frequently changed to meet the criteria of syndrome differentiation and treatment variation. Currently, a modified KXS (namely KXS2012) was prepared by optimizing the combinations of GR-PR and ATR-PO: the new herbal formula was shown to be very effective in animal studies. However, the cellular mechanism of KXS2012 against depression has not been fully investigated. Here, the study on KXS2012-induced neuronal differentiation in cultured PC12 cells was analyzed. In PC12 cultures, single application of KXS2012 showed no effect on the neuronal differentiation, but which showed robust effects in potentiating nerve growth factor (NGF)-induced neurite outgrowth and neurofilament expression. The potentiating effect of KXS2012 was mediated through NGF receptor, tropomyosin receptor kinase (Trk) A: because the receptor expression and activity was markedly up-regulated in the presence of KXS2012, and the potentiating effect was blocked by k252a, an inhibitor of Trk A. Our current results in cell cultures fully support the therapeutic efficacy of KXS2012 against depression