RESEARCH Open AccessWeight control interventions improvetherapeutic efficacy of dacarbazine inmelanoma by reversing obesity-induceddrug resistanceParmanand Malvi 1 , Balkrishna Chaube 1 , Shivendra Vikram Singh 1 , Naoshad Mohammad 1 , Vimal Pandey 1,3 ,Maleppillil Vavachan Vijayakumar 1 , Revathy Meenatheril Radhakrishnan 2 , Muralidharan Vanuopadath 2 ,Sudarslal Sadasivan Nair 2 , Bipin Gopalakrishnan Nair 2 and Manoj Kumar Bhat 1*AbstractBackground: Obesity-related cellular, metabolic, and molecular alterations have been shown to increase cancer risk andtumor progression and are associated with poorer therapeutic outcome in cancer patients. However, the impact ofobesity and weight-control interventions on the therapeutic response in melanoma is poorly understood.Methods: High fat diet (HFD)-induced obese mouse model was used in this study to evaluate the outcome ofdacarbazine (DTIC) therapy in melanoma. We employed LC-MS/MS to determine the quantity of the drug in tumor, andin various tissues. Unique in vitro approach was used to complement in vivo findings by culturing melanoma cells ineither conditioned medium (CM) obtained from differentiated adipocytes or in serum collected from experimental mice.Results: We report that diet-induced obesity impairs the outcome of DTIC therapy and reduces overall survival intumor-bearing mice. We provide evidence that obesity restricts the accessibility of DTIC to tumor tissue. Critically, uponcurtailing adiposity, accumulation and efficacy of DTIC is significantly improved. Moreover, using appropriate in vitroapproaches, we show that melanoma cells exhibit a drug-resistant phenotype when cultured in serum collected fromdiet-induced obese mice or in CM collected from 3T3-L1 adipocytes. The impaired therapeutic response to DTIC in obesestate is mediated by fatty acid synthase (FASN), caveolin-1 (Cav-1), and P-glycoprotein (P-gp). The response to DTIC andoverall survival were improved upon employing weight control interventions in the tumor-bearing HFD-fed (obese) mice.Conclusions: This study indicates that obesity not only supports rapid melanoma progression but also impairs theoutcome of chemotherapy, which can be improved upon employing weight control interventions. From clinically relevantpoint of view, our study exemplifies the importance of lifestyle interventions in the treatment of obesity-promoted cancers.Keywords: Obesity, Adipokines, Melanoma, Chemotherapy, Orlistat, Weight-control interventionsBackgroundObesity, owing to excess adiposity, is associated with in-creased risk of many cancer types [1–3]. With the unprece-dented surge in global epidemic of obesity and overweightpopulation, incidences of obesity-associated health compli-cations are also likely to increase [4, 5]. Adiposity-relatedcellular, metabolic, and molecular alterations are known topromote cancer risk and rapid tumor progression [3–7]and adversely affect the response to cancer therapy [8].However, the positive aspects of obesity management andweight control interventions on the outcome of chemo-therapy are not well understood.Adipose tissue, an endocrine organ, is considered as oneof the critical factors involved in tumor progression, angio-genesis, invasion, and metastasis [9–13]. Adipose tissueexpansion under persistent nutritional load alters serumprofile of adipokines, cytokines, and lipids [7, 10]. Thesechanges eventually create a state of chronic low-grade* Correspondence: manojkbhat@nccs.res.in; manojkbhat62@gmail.com1 Laboratory No. 6, National Centre for Cell Science (NCCS), Savitribai PhulePune University Campus, Ganeshkhind, Pune 411 007, IndiaFull list of author information is available at the end of the article© The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Malvi et al. Cancer & Metabolism (2016) 4:21 DOI 10.1186/s40170-016-0162-8
