fumarates and Colonic-Neoplasms

To examine the effects of aliskiren, a small-molecule renin inhibitor, on cancer cachexia and to explore the underlying mechanisms. A cancer cachexia model was established by subcutaneously injecting C26 mouse colon carcinoma cells into isogenic BALB/c mice. Aliskiren was administered intragastrically [10 mg/kg body weight (BW)] on day 5 (as a preventive strategy, AP group) or on day 12 (as a therapeutic strategy, AT group) after C26 injection. Mice that received no C26 injection (healthy controls, HC group) or only C26 injection but not aliskiren (cancer, CA group) were used as controls. BW, tumor growth, whole body functions, and survival were monitored daily in half of the mice in each group, whereas serum, tumors, and gastrocnemius muscles were harvested from the other mice after sacrifice on day 20 for further analysis. Aliskiren significantly alleviated multiple cachexia‑associated symptoms, including BW loss, tumor burden, muscle wasting, muscular dysfunction, and shortened survival. On the molecular level, aliskiren antagonized cachexia‑induced activation of the renin‑angiotensin system (RAS), systematic and muscular inflammation, oxidative stress, and autophagy‑lysosome as well as ubiquitin‑proteasome stimulation. In addition, early administration of aliskiren before cachexia development (AP group) resulted in more robust effects in alleviating cachexia or targeting underlying mechanisms than administration after cachexia development (AT group). Aliskiren exhibited potent anti‑cachexia activities. These activities were achieved through the targeting of at least four mechanisms underlying cachexia development: RAS activation, increase in systematic inflammation, upregulation of oxidative stress, and stimulation of autophagy-lysosome pathway (ALP) and ubiquitin-proteasome pathway (UPP).

Topics: Amides; Animals; Autophagy; Cachexia; Cell Line, Tumor; Colonic Neoplasms; Disease Models, Animal; Fumarates; Humans; Mice; Muscle, Skeletal; Muscular Atrophy; Oxidative Stress; Renin; Renin-Angiotensin System

Dimethyl fumarate (DMF) is a newly approved drug for the treatment of relapsing forms of multiple sclerosis and relapsing-remitting multiple sclerosis. Here, we investigated the effects of DMF and its metabolites mono-methylfumarate (MMF and methanol) on different gastrointestinal cancer cell lines and the underlying molecular mechanisms involved.. Cell viability was measured by the MTT or CCK8 assay. Protein expressions were measured by Western blot analysis. LDH release, live- and dead-cell staining, intracellular GSH levels, and mitochondrial membrane potential were examined by using commercial kits.. DMF but not MMF induced cell necroptosis, as demonstrated by the pharmacological tool necrostatin-1, transmission electron microscopy, LDH and HMGB1 release in CT26 cells. The DMF-induced decrease in cellular GSH levels as well as cell viability and increase in reactive oxygen species (ROS) were inhibited by co-treatment with GSH and N-acetylcysteine (NAC) in CT26 cells. DMF activated JNK, p38 and ERK MAPKs in CT26 cells and JNK, p38 and ERK inhibitors partially reversed the DMF-induced decrease in cell viability. GSH or NAC treatment inhibited DMF-induced JNK, p38, and ERK activation in CT26 cells. DMF but not MMF increased autophagy responses in SGC-7901, HCT116, HT29 and CT26 cancer cells, but autophagy inhibition did not prevent the DMF-induced decrease in cell viability.. DMF but not its metabolite MMF induced necroptosis in colon cancer cells through a mechanism involving the depletion of GSH, an increase in ROS and activation of MAPKs.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; Dimethyl Fumarate; Fumarates; Glutathione; HMGB1 Protein; Humans; L-Lactate Dehydrogenase; Maleates; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Methanol; Mice; Mitogen-Activated Protein Kinases; Necrosis; Reactive Oxygen Species

The bioreductive antitumour agent, mitomycin C (MMC), requires activation by reductive enzymes like NAD(P)H:quinone oxidoreductase 1 (NQO1). We used a novel approach to increase MMC efficacy by selectively inducing NQO1 in tumour cells in vivo. CD-1 nude mice were implanted with HCT116 cells, and fed control diet or diet containing 0.3% of the NQO1 inducer, dimethyl fumarate (DMF). The mice were then treated with saline, 2.0, 3.5 or 2.0 mg kg(-1) MMC and dicoumarol, an NQO1 inhibitor. The DMF diet increased NQO1 activity by 2.5-fold in the tumours, but had no effect in marrow cells. Mice given control diet/2.0 mg kg(-1) MMC had tumours with the same volume as control mice; however, mice given DMF diet/2.0 mg kg(-1) MMC had significantly smaller tumours. Tumour volumes in mice given DMF/2.0 mg kg(-1) MMC were similar to those in mice given control diet/3.5 mg kg(-1) MMC. Tumour inhibition was partially reversed in mice given DMF/2.0 mg kg(-1) MMC and dicoumarol. DMF diet/2.0 mg kg(-1) MMC treatment did not increase myelosuppression and did not produce any organ toxicity. These results provide strong evidence that dietary inducers of NQO1 can increase the antitumour activity of bioreductive agents like MMC without increasing toxicity.

Topics: Animals; Antibiotics, Antineoplastic; Bone Marrow; Colonic Neoplasms; Dicumarol; Diet Therapy; Dimethyl Fumarate; Drug Therapy, Combination; Enzyme Induction; Enzyme Inhibitors; Female; Fumarates; Humans; Mice; Mice, Nude; Mitomycin; NAD(P)H Dehydrogenase (Quinone); Tumor Cells, Cultured

Phase II detoxifying enzymes like NAD(P)H (quinone acceptor)oxidoreductase1 (NQO1), glutathione S-transferases (GST), and UDP-glucuronyltransferases (UGT) may play an important role in preventing carcinogen-induced cancers. Inducers of these enzymes have been shown to inhibit carcinogen-induced colon tumors in rat and mouse models. However, it has not been clearly demonstrated that NQO1 contributes to this effect. We examined the effect of NQO1 inducers on colon carcinogenesis using an aberrant crypt foci (ACF) rat model. Sprague-Dawley rats were fed control diet or diet containing 400 ppm dimethyl fumarate or 200 ppm oltipraz for 7 days, and Phase II enzymes in rat colon and liver were measured. Dimethyl fumarate significantly increased NQO1 and GST activities in colon and liver but did not increase UGT activities in these tissues. In contrast, oltipraz significantly increased NQO1 activities in colon and liver and produced a small increase in GST activity in the liver but did not increase GST activity in the colon or UGT activities in the liver or colon. Sprague Dawley rats were fed control diet or diet containing 200 ppm oltipraz and then treated with the carcinogens azoxymethane or methyl nitrosourea. Both carcinogens produced ACF in all of the rat colons, but rats fed oltipraz diet had significantly fewer ACF than those fed control diet. This protective effect was reversed in rats treated with the NQO1 inhibitor, dicoumarol. However, treatment with oltipraz did not alter the distribution of crypt multiplicities in the ACF. These studies demonstrated that induction of NQO1 plays a significant role in inhibiting initiation of carcinogen-induced ACF in Sprague-Dawley rats. This provides the first direct evidence that NQO1 may play a role in preventing colon cancer. The study also found that oltipraz added to the diet of Sprague-Dawley rats selectively increased NQO1 activity in colon mucosa with no increase in GST and UGT activities in these tissues. Thus, this model will be useful for further investigating the role of NQO1 in prevention of colon cancer.

Topics: Animals; Anticarcinogenic Agents; Carcinogens; Colon; Colonic Neoplasms; Dimethyl Fumarate; Disease Models, Animal; Enzyme Induction; Fumarates; Glucuronosyltransferase; Glutathione Transferase; Inactivation, Metabolic; Intestinal Mucosa; Liver; Male; NAD(P)H Dehydrogenase (Quinone); NADP; Pyrazines; Radiation-Sensitizing Agents; Rats; Rats, Sprague-Dawley; Thiones; Thiophenes