We thus longitudinally monitored body weight development in non-tumor and tumor bearing mice (Fig.?1a, BMS-740808 b). and the associated cachexia was evaluated using body weight loss or tumor volume as interruption criteria. Results Cisplatin accelerated body weight loss and tended to exacerbate skeletal muscle loss in cachectic animals, likely due to some toxicity CTSD of this anti-cancer agent. Administration of CDD866 alone or in combination with cisplatin protected from skeletal muscle weight loss compared to animals receiving only cisplatin, corroborating that ActRII inhibition remains fully efficacious under cisplatin treatment. In contrast, everolimus treatment alone significantly protected the tumor-bearing mice against skeletal muscle weight loss caused by CT-26 tumor. CDD866 not only remains efficacious in the presence of everolimus but also showed a nonsignificant trend for an additive effect on reversing skeletal muscle weight loss. Importantly, both combination therapies slowed down time-to-progression. Conclusions Anti-ActRII blockade is an effective intervention against cancer cachexia providing benefit even in the presence of anti-cancer therapies. Co-treatment comprising chemotherapies and ActRII inhibitors might constitute a promising new approach to alleviate chemotherapy- and cancer-related wasting conditions and extend survival rates in cachectic cancer patients. Electronic supplementary material The online version of this article (doi:10.1186/s13395-016-0098-2) contains supplementary material, which is available to authorized users. non-fat milk powder. Primary antibodies phospho-SMAD3 (Millipore BMS-740808 #04 1042 diluted 1:1000) and -tubulin (Sigma T6199 Diluted 1:5000) were incubated in TBS with 0.1?% Tween 20 and 5?%?non-fat milk powder and secondary antibodies in TBS with 0.1?% Tween 20, 0.05?% SDS, and 5?% non-fat milk. Immunoreactivity was detected by SuperSignal West Femto Maximum Sensitivity Substrate (Thermo Scientific) and exposed to film or acquired by FusionSpectra. Quantitative determination of mTOR and IL-6 was performed using an assay kit (catalog number K15170D for phospho (Ser 2448)/total mTOR, K15048D for IL-6) from MesoScale Discovery using a MesoScale Discovery reader according to the manufacturers instruction. Gene expression profiling RNA samples were extracted from the gastrocnemius muscle using the Trizol reagent (Invitrogen). Reverse transcription was performed with random hexamers on 1?g of total RNA using a high-capacity reverse transcription kit (Applied Biosystems), and the reaction mixture was diluted 100 times for amplification. PCRs were performed in duplicates in 384-well plates on a CFX384 cycler (Bio-Rad, Hercules, CA, USA) using specific TaqMan probes (Applied Biosystems). Data were normalized to two housekeeping genes using the CT threshold cycle (CT) method. Statistical analysis Values are expressed as mean??SEM. Statistical analysis was carried out using Holm-Sidaks multiple comparison test following analysis of variance to compare the treatment groups to the control groups (non-tumor and tumor-bearing), anti-cancer agent alone (cisplatin or everolimus) or CDD866 alone in the therapeutic intervention study, and Dunns multiple comparisons test for time-to-progression study. Differences were considered to be significant when the probability value was 0.05. Statistical analyses were performed by GraphPad Prism (GraphPad Software, Inc., La Jolla, CA, USA). Body weight was expressed as percentage change from day 0 as the start of treatment. Tumor volumes in cubic millimeters were calculated according to the formula (length??width2)/2. Muscle weight was normalized to the body weight on the day of cell inoculation (initial body weight) and then expressed as percentage change BMS-740808 from the non-tumor control group. Results Cancer cachexia, i.e., muscle wasting associated with cancer and also with some standard of care interventions, dramatically affects patient quality of life, anti-cancer treatment effectiveness, and overall survival. We characterized our anti-cachexia agent, CDD866, and examined its potential benefit in the context of co-therapies in CT-26 mouse colon cancer cachexia model, in which tumor is insensitive to anti-ActRII intervention. Chemotherapy constitutes a standard of care in many cancers and is frequently used as first-line therapy. Intriguingly, certain chemotherapeutic agents, which are routinely administered to hinder tumor growth, precipitate muscle wasting. Indeed, administration of cisplatin is known to exacerbate body weight and muscle loss in mouse cancer cachexia. We thus first evaluated whether CDD866 could counter cisplatin-induced wasting without affecting the efficacy of the chemotherapy. CDD866 prevents cisplatin-induced body weight loss Extensive body weight loss has emerged as a key determinant of cancer-related death. We thus longitudinally monitored body.
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- 2 Dual mTOR inhibitors inhibit bladder cancer cell growth in a dose-dependent manner
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