Straughn Alex R, Kelm Natia Q, Kakar Sham S
James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States.
Department of Physiology, University of Louisville, Louisville, KY, United States.
Front Cell Dev Biol. 2021 Feb 25;9:636498. doi: 10.3389/fcell.2021.636498. eCollection 2021.
Cachexia is a complex wasting syndrome that overwhelmingly affects the majority of late-stage cancer patients. Additionally, there are currently no efficacious therapeutic agents to treat the muscle atrophy induced by the cancer. While several preclinical studies have investigated the molecular signals orchestrating cachexia, very little information exists pertaining to ovarian cancer and the associated cachexia. Work from our lab has recently demonstrated that the steroidal lactone Withaferin A (WFA) is capable of attenuating the atrophying effects of ovarian cancer in a preclinical mouse model. However, it remained to be determined whether WFA's effect was in response to its anti-tumorigenic properties, or if it was capable of targeting skeletal muscle directly. The purpose of this study was to uncover whether WFA was capable of regulating muscle mass under tumor-free and tumor-bearing conditions. Treatment with WFA led to an improvement in functional muscle strength and mass under tumor-bearing and naïve conditions. WFA and ovarian cancer were observed to act antagonistically upon critical skeletal muscle regulatory systems, notably myogenic progenitors and proteolytic degradation pathways. Our results demonstrated for the first time that, while WFA has anti-tumorigenic properties, it also exerts hypertrophying effects on skeletal muscle mass, suggesting that it could be an anti-cachectic agent in the settings of ovarian cancer.
恶病质是一种复杂的消耗综合征，绝大多数晚期癌症患者都会受到其严重影响。此外，目前尚无有效的治疗药物来治疗癌症引起的肌肉萎缩。虽然有几项临床前研究调查了引发恶病质的分子信号，但关于卵巢癌及其相关恶病质的信息却非常少。我们实验室最近的研究表明，甾体内酯Withaferin A（WFA）在临床前小鼠模型中能够减轻卵巢癌的萎缩效应。然而，WFA的作用是因其抗肿瘤特性，还是能够直接作用于骨骼肌，仍有待确定。本研究的目的是揭示WFA在无肿瘤和荷瘤条件下是否能够调节肌肉质量。在荷瘤和未荷瘤条件下，用WFA治疗可改善功能性肌肉力量和质量。观察到WFA与卵巢癌对关键的骨骼肌调节系统，特别是肌源性祖细胞和蛋白水解降解途径，具有拮抗作用。我们的结果首次表明，虽然WFA具有抗肿瘤特性，但它也对骨骼肌质量产生肥大作用，这表明它可能是卵巢癌背景下的一种抗恶病质药物。
