BackgroundObesity-related cellular, metabolic, and molecular alterations have been shown to increase cancer risk and tumor progression and are associated with poorer therapeutic outcome in cancer patients. However, the impact of obesity and weight-control interventions on the therapeutic response in melanoma is poorly understood.MethodsHigh fat diet (HFD)-induced obese mouse model was used in this study to evaluate the outcome of dacarbazine (DTIC) therapy in melanoma. We employed LC-MS/MS to determine the quantity of the drug in tumor, and in various tissues. Unique in vitro approach was used to complement in vivo findings by culturing melanoma cells in either conditioned medium (CM) obtained from differentiated adipocytes or in serum collected from experimental mice.ResultsWe report that diet-induced obesity impairs the outcome of DTIC therapy and reduces overall survival in tumor-bearing mice. We provide evidence that obesity restricts the accessibility of DTIC to tumor tissue. Critically, upon curtailing adiposity, accumulation and efficacy of DTIC is significantly improved. Moreover, using appropriate in vitro approaches, we show that melanoma cells exhibit a drug-resistant phenotype when cultured in serum collected from diet-induced obese mice or in CM collected from 3T3-L1 adipocytes. The impaired therapeutic response to DTIC in obese state is mediated by fatty acid synthase (FASN), caveolin-1 (Cav-1), and P-glycoprotein (P-gp). The response to DTIC and overall survival were improved upon employing weight control interventions in the tumor-bearing HFD-fed (obese) mice.ConclusionsThis study indicates that obesity not only supports rapid melanoma progression but also impairs the outcome of chemotherapy, which can be improved upon employing weight control interventions. From clinically relevant point of view, our study exemplifies the importance of lifestyle interventions in the treatment of obesity-promoted cancers.

中文翻译：

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体重控制干预通过逆转肥胖引起的耐药性来提高达卡巴嗪治疗黑色素瘤的疗效

背景肥胖相关的细胞、代谢和分子改变已被证明会增加癌症风险和肿瘤进展，并与癌症患者较差的治疗结果相关。然而，肥胖和体重控制干预对黑色素瘤治疗反应的影响知之甚少。方法本研究使用高脂肪饮食（HFD）诱导的肥胖小鼠模型来评估达卡巴嗪（DTIC）治疗黑色素瘤的效果。我们采用 LC-MS/MS 来确定药物在肿瘤和各种​​组织中的数量。通过在从分化的脂肪细胞获得的条件培养基 (CM) 或从实验小鼠收集的血清中培养黑色素瘤细胞，使用独特的体外方法来补充体内发现。结果我们报告说，饮食诱导的肥胖会损害 DTIC 治疗的结果并降低荷瘤小鼠的总体存活率。我们提供证据表明肥胖限制了 DTIC 对肿瘤组织的可及性。至关重要的是，在减少肥胖后，DTIC 的积累和功效得到显着改善。此外，使用适当的体外方法，我们表明黑色素瘤细胞在从饮食诱导的肥胖小鼠收集的血清或从 3T3-L1 脂肪细胞收集的 CM 中培养时表现出耐药表型。肥胖状态下对 DTIC 的治疗反应受损是由脂肪酸合酶 (FASN)、caveolin-1 (Cav-1) 和 P-糖蛋白 (P-gp) 介导的。在荷瘤 HFD 喂养（肥胖）小鼠中采用体重控制干预后，对 DTIC 的反应和总体存活率得到改善。结论这项研究表明，肥胖不仅支持黑色素瘤的快速进展，而且还会损害化疗的结果，这可以通过采用体重控制干预措施来改善。从临床相关的角度来看，我们的研究证明了生活方式干预在治疗肥胖促进的癌症中的重要性。