Yumin Hu

Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

PURPOSEnTo evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS).nnnPATIENTS AND METHODSnPatients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m(2) intravenously (IV) daily × 3 (days 4 to 6), and cytarabine 1.5 g/m(2) IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely.nnnRESULTSnAfter a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival.nnnCONCLUSIONnThe combination of vorinostat with idarubicin and cytarabine is safe and active in AML.

Mild Cu(I)-Catalyzed Cascade Reaction of Cyclic Diaryliodoniums, Sodium Azide, and Alkynes: Efficient Synthesis of Triazolophenanthridines

Linear iodoniums are widely used as arylating reagents. However, cyclic diaryl idodoniums are ignored despite their potential to initiate dual arylations, atom and step economically. In our current work, a three-component cascade reaction of cyclic diaryliodoniums, sodium azide, and alkynes has been successfully achieved under mild conditions, catalyzed by cheap copper species. The regioselectivity associated with unsymmetrical iodoniums was enhanced by installing two methyls ortho and para to the I(III) center. The reaction enables a rapid access to a variety of complex molecules, triazolophenanthridine derivatives.

Visible-light-induced radical cyclization of trifluoroacetimidoyl chlorides with alkynes: catalytic synthesis of 2-trifluoromethyl quinolines.

351591 (Scheme 1, II) has been identified as a potent and highly selective type 4 phosphodiesterase (PDE4) inhibitor. Quinoline-based compound III (Scheme 1), target DNA topoisomerase IV, and DNA gyrase, can be used as antituberculosis agents. As a consequence, the development of an efficient method for the synthesis of 2-trifluoromethyl quinoline derivatives has become a subject of great interest. Among the methods to construct such structures, transition-metal-catalyzed reactions of trifluoroacetimidoyl halides with alkynes have been studied extensively in recent years. For example, Uneyama et al. reported a one-pot synthesis of 2-trifluoromethyl quinolines by Rh-catalyzed cyclization of N-aryl trifluoroacetimidoyl chlorides with alkynes. Wu and co-workers developed a Cu-catalyzed coupling reaction and subsequent cyclization to construct 4-substituted 2-fluoromethylated quinolines. These reported reactions employ easily available trifluoroacetimidoyl halides as the starting materials, albeit with poor regioselectivity in some cases. Compared to transition-metal-catalyzed reactions, the radical pathway involving intermolecular addition of trifluoroACHTUNGTRENNUNGacetimidoyl radical to alkynes and subsequent annulation has received less attentions. Generation of trifluoroacetimidoyl radical has been examined by three different pathways, including: 1) tin-radical-mediated deiodination of imidoyl iodides (Scheme 2a); 2) homolytic cleavage of the

Xc - inhibitor sulfasalazine sensitizes colorectal cancer to cisplatin by a GSH-dependent mechanism

Sulfasalazine (SSZ) is an anti-inflammatory drug that has been demonstrated to induce apoptosis and tumor regression through inhibition of plasma membrane cystine transporter xc(-). Cysteine is a rate-limiting precursor for intracellular glutathione (GSH) synthesis, which is vital for compound detoxification and maintaining redox balance. Platinum-based chemotherapy is an important regimen used in clinics for various cancers including colorectal cancer (CRC). We hypothesized that targeting xc(-) transporter by SSZ may annihilate cellular detoxification through interruption of GSH synthesis and may enhance the anti-cancer activity of cisplatin (CDDP) by increasing drug transport. In the present study, we revealed that xCT, the active subunit of xc(-), is highly expressed in CRC cell lines and human colorectal carcinoma tissues compared with their normal counterparts. SSZ effectively depleted cellular GSH, leading to significant accumulation of reactive oxygen species and growth inhibition in CRC cells. In contrast, the normal epithelial cells of colon origin were less sensitive to SSZ, showing a moderate ROS elevation. Importantly, SSZ effectively enhanced the intracellular platinum level and cytotoxicity of CDDP in CRC cells. The synergistic effect of SSZ and CDDP was reversed by antioxidant N-acetyl-L-cysteine (NAC). Together, these results suggest that SSZ, a relatively non-toxic drug that targets cystine transporter, may, in combination with CDDP, have effective therapy for colorectal cancer.

Synthesis of N -acyl- N, O -acetals mediated by titanium ethoxide

N-Acyl-N,O-acetals are present in a number of bioactive natural products, and this unusual functional group can act as a synthetic precursor to unstable reactive N-acylimines. In this paper, a variety of N-acyl-O-ethyl-N,O-acetals was concisely prepared under mild conditions mediated by titanium ethoxide (Ti(OEt)4). The method also offers a new strategy to make other O-alkyl-N,O-acetals. Furthermore, this strategy was extended to the synthesis of an analogue of the natural product turtschamide.

Synthesis of 2-trifluoromethyl indoles via visible-light induced intramolecular radical cyclization

A visible-light induced intramolecular radical cyclization of N-[2-(alkynyl)phenyl]trifluoroacetimidoyl chlorides is described. The reaction allows the rapid construction of diverse 2-trifluoromethyl-3-acylindoles in a sequential C–C and C–O bond formation process under mild conditions.

Metabolic alterations and drug sensitivity of tyrosine kinase inhibitor resistant leukemia cells with a FLT3/ITD mutation

Internal tandem duplication (ITD) of the juxtamembrane region of FMS-like tyrosine kinase-3 (FLT3) receptor is a common type of mutation in adult acute myeloid leukemia (AML), and patient response to FLT3 inhibitors appears to be transient due to the emergence of drug resistance. We established two sorafenib-resistant cell lines carrying FLT3/ITD mutations, including the murine BaF3/ITD-R and human MV4-11-R cell lines. Gene expression profile analysis of the resistant and parental cells suggests that the highest ranked molecular and cellular functions of the differentially expressed genes are related to mitochondrial dysfunction. Both murine and human resistant cell lines display a longer doubling time, along with a significant inhibition of mitochondrial respiratory chain activity and substantial upregulation of glycolysis. The sorafenib-resistant cells exhibit increased expression of a majority of glycolytic enzymes, including hexokinase 2, which is also highly expressed in the mitochondrial fraction and is associated with resistance to apoptotic cell death. The sorafenib-resistant cells are collaterally sensitive to a number of glycolytic inhibitors including 2-deoxyglucose and 3-bromopyruvate propylester. Our study reveals a metabolic signature of sorafenib-resistant cells and suggests that glycolytic inhibition may override such resistance and warrant further clinical investigation.

Relayed Regioselective Alkynylation/Olefination of Unsymmetrical Cyclic Diaryliodonium Species Catalyzed by Cu and Pd: Affording Fluorescent Cytotoxic Benzoxazoles.

Although cyclic diaryliodonium species have the potential to act as valuable synthons for cascade transformations, they still remain largely unexplored. The regioselectivity associated with unsymmetrical cyclic diaryliodonium species has previously been known to pose a challenge. A regioselective relayed alkynylation and olefination of unsymmetrical cyclic diaryliodonium species has been achieved by installation of a directing amido group. These relayed transformations were delayed until an oxazole ring had formed, delivering a series of unique fluorescent benzoxazoles. Moreover, some of these synthetic benzoxazoles showed apparent inhibitory activity against malignant cancer cells. Further confocal visualization revealed that benzoxazoles targeted cell nuclei. These findings might provide a novel structural scaffold to develop desirable anticancer agents.

Selective killing of K-ras–transformed pancreatic cancer cells by targeting NAD(P)H oxidase

IntroductionOncogenic activation of the K-ras gene occurs in >90% of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy. Increase of reactive oxygen species (ROS) has also been observed in a wide spectrum of cancers. This study aimed to investigate the mechanistic association between K-ras–induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer.MethodsROS level, NADPH oxidase (NOX) activity and expression, and cell invasion were examined in human pancreatic duct epithelial E6E7 cells transfected with K-rasG12V compared with parental E6E7 cells. The cytotoxic effect and antitumor effect of capsaicin, a NOX inhibitor, were also tested in vitro and in vivo.ResultsK-ras transfection caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositol 3′-kinase (PI3K) pathway. Importantly, capsaicin preferentially inhibited the enzyme activity of NOX and induced severe ROS accumulation in K-ras–transformed cells compared with parental E6E7 cells. Furthermore, capsaicin effectively inhibited cell proliferation, prevented invasiveness of K-ras–transformed pancreatic cancer cells, and caused minimum toxicity to parental E6E7 cells. In vivo, capsaicin exhibited antitumor activity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells.ConclusionsK-ras oncogenic signaling causes increased ROS stress through NOX, and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors. Our study provides a basis for developing a novel therapeutic strategy to effectively kill K-ras–transformed cells through a redox-mediated mechanism.

Glyceraldehyde-3-phosphate dehydrogenase promotes cancer growth and metastasis through upregulation of SNAIL expression

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plays an important role in multiple cellular functions including metabolism and gene transcription. Our previous study showed that GAPDH expression was elevated in colon cancer and further upregulated in liver metastatic tissues, suggesting a possilbe role of GAPDH in promoting cancer metastasis. The present study was designed to investigate the underlying mechanism, using multiple experimental approaches including genetic silencing of GAPDH expression by short hairpin RNA (shRNA) and biochemcial/molecular analyses of the key events involved in glycolytic metabolism and epithelial-mesenchymal transition (EMT). We showed that silencing of GAPDH expression resulted in a significant reduction of glycolysis in colon cancer cell lines, accompanied by a decrease in cell proliferation and an apparent change in cell morphology associated with alterations in actin expression and phalloidine staining patterns. Furthermore, GAPDH suppression also caused a downregulation of gene expression involved in cancer stem-like cells and EMT. CHIP assay and co-immunoprecipitation revealed that GAPDH physically interacted with the transcriptional factor Sp1 and enhance the expression of SNAIL, a major regulator of EMT. Suppression of GAPDH expression resulted in a signficant decrease in SNAIL expression, leading to inhibition of EMT and attenuation of colon cancer cell migration inxa0vitro and reduced metastasis inxa0vivo. Overall, the present study suggests that GAPDH plays an important role in cancer metastasis by affecting EMT through regulation of Sp1-mediated SNAIL expression.