No approved therapy exists for cancer-associated cachexia. The colon-26 mouse model of cancer cachexia mimics recent late-stage clinical failures of anabolic anti-cachexia therapy and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx-024. The histone deacetylase inhibitor (HDACi) AR-42 exhibited anticachectic activity in this model. We explored combined SARM/AR-42 therapy as an improved anti-cachectic treatment paradigm. A reduced dose of AR-42 provided limited anti-cachectic benefits, but, in combination with GTx-024, significantly improved body weight, hindlimb muscle mass, and grip strength versus controls. AR-42 suppressed the IL-6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx-024-mediated bcatenin target gene regulation was apparent in cachectic mice only when combined with AR-42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.

BackgroundCancer cachexia impacts the majority of advanced cancer patients but no approved anticachexia therapeutic exits. Recent late stage clinical failures of anabolic anti-cachexia therapy revealed heterogeneous responses to anabolic therapies and a limited ability to translate improved body composition into functional benefit. It is currently unclear what governs anabolic responsiveness in cachectic patient populations. Methods We evaluated anabolic androgen therapy combined with the novel anti-cachectic histone deacetylase inhibitor (HDACi) AR-42 in a series of studies using the C-26 mouse model of experimental cachexia. The ability of treatment to suppress tumor-mediated catabolic signaling and promote anabolic effects were characterized. Results Anabolic anti-cachexia monotherapy with the selective androgen receptor modulator (SARM) GTx-024 or enobosarm had no impact on cachectic outcomes in the C-26 model. A minimally effective dose of AR-42 provided mixed anti-cachectic benefits when administered alone but when combined with GTx-024 significantly improved bodyweight (p <0.0001), hind limb muscle mass (p <0.05), and voluntary grip strength (p <0.0001) versus tumor bearing controls. Similar efficacy resulted from the combination of AR-42 with multiple androgens. Anti-cachectic efficacy was associated with the ability to reverse pSTAT3 and atrogene induction in gastrocnemius muscle of tumor-bearing animals in the absence of treatment-mediated changes in serum IL-6 or LIF. Conclusions Anabolic GTx-024 monotherapy is incapable of overcoming catabolic signaling in the C-26 model of experimental cachexia. Anti-cachectic androgen therapy is greatly improved by successful blockade of STAT3 mediated atrophy with AR-42. Combined androgen and HDAC inhibitor administration represents promising approach to improve anabolic response in cachectic patient populations.

Patients with ovarian cancer are typically diagnosed at an advanced stage, resulting in poor prognosis since there are currently no effective early-detection screening tests for women at average-risk for ovarian cancer. Here, we investigated the effects of MT-6, a derivative of moscatilin, in ovarian cancer cells. Our investigation showed that MT-6 inhibited the proliferation and viability of ovarian cancer cells with submicromolar IC 50 values. MT-6-treated SKOV3 cells showed significant cell cycle arrest at G2/M phase, followed by an increase in the proportion of cells in a sub-G1 phase. In addition, MT-6 induced a concentration-dependent increase in mitotic markers, mitotic kinases, cell cycle regulators of G2/M transition, and apoptosis-related markers in ovarian cancer cells. MT-6 treatment also induced mitochondrial membrane potential loss, JNK activation, and DR5 expression. Cotreatment of cells with the JNK inhibitor SP600125 considerably attenuated MT-6-induced apoptosis, mitochondria membrane potential loss, DR5 upregulation, and suppression of cell viability. MT-6 also inhibited tumor growth in an SKOV3 xenograft model without significant body weight loss. Together, our findings suggest that MT-6 is a potent anticancer agent with tumor-suppressive activity in vitro and in vivo that could be further investigated for ovarian cancer therapy in the future.Among malignant gynecological tumors, patients with ovarian cancer have a high mortality rate owing to late stage diagnosis 1 . In addition to debulking surgery, the standard treatment for ovarian cancer is platinum-based chemotherapy in combination with taxane cytotoxic drugs, but a majority of these patients ultimately relapse within 2 years 2 . Therefore, prolonged courses of chemotherapy or better therapeutic options need to be continuously investigated. Antimitotic agents, which produce significant cytotoxicity, have been used effectively in the clinic for decades in patients with a variety of malignancies, including breast cancer, ovarian cancer, and lung cancer 3,4 . Although current trends of drug development for cancer treatment emphasize target-oriented approaches to enhance specificity so as to reduce unwanted side effects, novel antimitotic drugs still retain significant clinical value and have yielded promising outcomes [5][6][7] . During the cell cycle, progression from G2 to M phase requires activation of the Cdk1/cyclin B1 complex, which is controlled by phosphorylation at different sites of Cdk1 8,9 . Antimitotic agents usually target microtubule dynamics and cell-cycle regulatory proteins, whose main function is to properly coordinate cell division in mammalian cells. Consequently, antimitotic drugs cause cell cycle dysregulation (mitotic arrest) followed by aberrant division and cell death 10 . Apoptosis, the best-known form of programmed cell death, mainly involves activation of a cascade of caspase that is triggered by the extrinsic (death receptor) or intrinsic (mitochondrial) apoptotic pathways and leads to characteristic biochemic...