MYC directs transcription of MCL1 and eIF4E genes to control sensitivity of gastric cancer cells toward HDAC inhibitors.

Histone deacetylases (HDACs) control fundamental physiological processes such as proliferation and differentiation. HDAC inhibitors (HDACi) induce cell cycle arrest and apoptosis of tumor cells. Therefore, they represent promising cancer therapeutics that appear particularly useful in combination therapies. Although HDACi are tested in current clinical trials, the molecular mechanisms modulating the cellular responses toward HDACi are incompletely understood. To gain insight into pathways that limit HDACi efficacy in gastric cancer, we treated a panel of gastric cancer cells with the clinically relevant HDACi suberoylanilide hydroxamic acid (SAHA). We report that higher expression levels of the anti-apoptotic BCL2 family members MCL1 and BCL(XL) were detectable in cells with high inhibitory concentration 50 (IC(50)) values for SAHA. Using RNAi, we show that MCL1 and BCL(XL) lower the efficacy of SAHA. To find strategies to interfere with MCL1 and BCL(XL) expression, we investigated molecular regulation of both proteins. We show that specific siRNAs against c-MYC as well as pharmacological inhibition of this cancer-relevant transcription factor reduced MCL1 and BCL(XL) expression. Subsequently, we observed an increase in SAHA efficacy. Our data furthermore demonstrate that two different molecular mechanisms are responsible for the modulation of these factors. Whereas c-MYC controls transcription of MCL1 directly, regulation of BCL(XL) was due to c-MYC's capability to regulate the eIF4E gene, which encodes a rate-limiting factor of eukaryotic translation. Our data reveal a new molecular mechanism for how c-MYC controls cell autonomous apoptosis and provide a rationale for a concerted inhibition of HDACs and c-MYC in gastric cancer

Frühdiagnose und Behandlungseinschätzung des Magenkrebses

To identify potential biomarker genes and to develop novel therapeutic strategies for gastric cancer, protein and mRNA expression levels of cathepsins and MMPs were investigated in gastric cancer cell lines and tissues. Ex vivo detection indicated that the near infra red fluorescent probes were specifically activated in stomach tumor of CEA-TAG mice. Furthermore, the observation that c-MYC controls expression of BCLXL (indirectly) MCL1 (directly) might argue that c-MYC is an important mediator of therapeutic resistance of gastric cancer cells and its inhibition applied in combination with SAHA might be a rationally based therapeutic option for gastric cancer.Um potentielle Biomarker zur Frühdiagnose des Magenkarzinoms zu identifizieren, wurde die Expression von Cathepsinen im Magenkarzinom untersucht. Mittels einer durch Cathepsine aktivierbaren Fluoreszenzsonde wurden endogene Magen-karzinome einer CEA-TAG Mauslinie ex vivo nachgewiesen. Des Weiteren wurden Therapieresistenzmechanismen im Magenkarzinom untersucht. Hierbei konnte eine durch c-MYC gesteuerte und durch BCLXL und MCL1 vermittelte Resistenz auf HDAC Inhibition beobachtet werden. Deshalb stellt die kombinierte Inhibition von c-MYC- und HDAC eine viel versprechende Therapieoption des Magenkarzinoms dar

Chemopreventive Activity of 80% Methanol Leaf Extract of Vernonia auriculifera Hiern (Asteraceae) Against Dimethylhydrazine-Induced Colorectal Carcinogenesis in Rats

Yohannes Tsegyie Wondmkun,1 Ephrem Engidawork,1 Wajana Lako Labisso,2 Anteneh Belete,3 Solomon Tesfaye,1 Yonas Girma Shumiye2 1Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, Addis Ababa University, Addis Ababa, Ethiopia; 2Department of Pathology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia; 3Department of Pharmaceutics and Social Pharmacy, School of Pharmacy, Addis Ababa University, Addis Ababa, EthiopiaCorrespondence: Ephrem Engidawork; Yohannes Tsegyie, Email [email protected]; [email protected]; [email protected]: Vernonia auriculifera Hiern (Asteraceae) is among Ethiopian herbal medicines that are traditionally used to treat skin and gastrointestinal cancers. In this study, the chemopreventive potential of Vernonia auriculifera leaf extract in dimethylhydrazine (DMH)-induced colorectal carcinogenesis in rats was investigated.Methods: Rats were assigned to nine groups (normal, positive, and negative control groups, and three pre- and three post-initiation groups). Except for the normal control group (administered with 1 mL/100 g distilled water), the remaining eight groups were given DMH (20 mg/kg) intraperitoneally (ip) for 15 consecutive weeks to induce colorectal tumours. The extract was given orally to the pre-initiation and post-initiation groups at doses of 100, 200, and 400 mg/kg before and after the induction of cancer, respectively. The positive control group was treated with aspirin (60 mg/kg/day) orally for the whole experimental period. Parameters including body weight, average tumour number, size, progression, incidence, total cholesterol, serum total protein, and triglyceride levels were determined. The cytotoxic activity of the extract in Caco-2 cells was evaluated using the MTT assay, and the antioxidant activity of the extract was also assessed using 2.2-diphenyl-1-picrylhydrazine (DPPH) and reducing power methods. Moreover, total phenol and flavonoid contents were determined using appropriate methods.Results: Rats treated with the extract showed a lower incidence of up to 50% in the pre-initiation higher dose, average number (p< 0.05),and size (p< 0.05) of tumours compared to untreated rats. It also inhibited colorectal cancer-associated increases in serum total cholesterol and triglycerides. The extract’s IC50 value in the MTT assay was found to be higher than 200 μg/mL. The extract had an IC50 of 74.88 ± 0.86 μg/mL and 84.69 ± 2.02 μg/mL in the reducing power and DPPH assays, respectively. Total flavonoid and phenol contents were 14.51 ± 0.41 mg quercetin acid equivalent/gm and 47.37 ± 0.72 mg gallic acid equivalent/gm of the crude extract, respectively.Conclusion: The findings collectively indicated that the leaves of V. auriculifera possess chemopreventive activity, probably mediated through antioxidant mechanisms, which supports the traditional claim.Keywords: antioxidant, cytotoxicity, colorectal cancer, pre-initiation, post-initiation, Vernonia auriculifer

Investigation of the effect of coffee on body weight, serum glucose, uric acid and lipid profile levels in male albino Wistar rats feeding on high-fructose diet

AbstractCoffee is one of the most commonly consumed beverages in the worldwide and is assumed to have protective effects against metabolic syndrome. The present study was aimed at investigating the effect of coffee on body weight, serum glucose, uric acid and lipid profile levels in male albino Wistar rats feeding on high fructose diet. A post-test experimental study was conducted on a total of 30 (9–10 weeks old) male albino Wistar rats. The rats were divided into 6 groups: group I (normal control)-fed on standard chow and plain tap water only; group II (fructose control)-fed on standard chow and 20% of fructose solution; group III–VI (treatment groups)-fed on standard chow, 20% of fructose solution and treated with 71, 142, 213 and 284 mg/kg body weight/day of coffee respectively for six weeks. At the end, body weight, serum glucose, uric acid and lipid profile levels were investigated. Data was entered and cleared by epi-data software version 3.1 and analyzed by one way ANOVA followed by Tukey post hoc multiple comparison tests using SPSS V. 23.00. Statistical significance was considered at p &lt; 0.05. The results showed that body weight, fasting serum glucose and uric acid levels significantly lowered in rats treated with 213 (p = 0.047; 0.049; 0.026) and 284 (p = 0.035; 0.029; 0.010) mg/kg body weight/day of coffee compared to fructose control group. Fasting serum triglycide (TG) and low density lipoprotein (LDL-C) levels showed significant reduction in rats treated with 284 mg/kg body weight/day of coffee as compared to fructose control group (p = 0.031; 0.046) respectively. In conclusion, treating rats with coffee decreased body weight, fasting serum glucose, uric acid, TC, TG and LDL-C, and increased HDL-C in a dose dependent manner in rats feeding on high fructose diet, suggesting that coffee consumption may be helpful in ameliorating metabolic syndrome.</jats:p