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Application of Histone Deacetylase Inhibitor AR-42 in the Treatment of Cancer-induced Cachexia

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2017, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Cancer is among the top five leading causes of death in the United States. Part of the contributing of death comes from cancer cachexia, a debilitating condition characterized by depletion of skeletal muscle with or without adipose tissue wasting, which leads to pronounced weight loss, weakness, fatigue, lower tolerance to chemotherapy and radiation treatment, and ultimately decreased survival. Cachexia occurs in more than 50% of cancer patients, and is particularly prevalent in pancreatic cancer patients, of whom over 80% suffer from cachexia. Thus, the development of effective therapies against cachexia has tremendous potential to improve quality of life and increase survival of pancreatic cancer patients. However, no effective treatments for cachexia currently exist. In this study, we report the in vivo efficacy of the HDAC inhibitor, AR-42, provided significant protective effects against cachexia in three different animal models of cancer-induced cachexia. AR-42, a histone deacetylase (HDAC) inhibitor, reduced cachexia-induced losses in skeletal muscle mass, adipose tissue mass, preserved muscle function and prolonged survival in C-26 tumor-bearing mice. Importantly, AR-42 was much more effective than two other HDAC inhibitors, vorinostat and romidepsin, to suppress cachexia induced muscle atrophy. Suppression of the mRNA expression of the E3 ligases Atrogin-1/MAFbx and MuRF1 in the skeletal muscle of tumor-bearing mice can be found in all AR-42 treated mice, which indicated the ability of AR-42 to inhibit cancer cachexia progression. Cytokine profiling and RNA-seq analyses revealed that the suppressive effect of AR-42 on cachectic muscle atrophy arises from its diverse effects on tumor-induced changes in inflammatory cytokine production and multiple transcriptional programs. Our previous studies indicated that AR-42 showed potent ability to suppress muscle catabolic effects in cancer cachexia models. Therefore, to further improve AR-42, we hypothesized that co-treat AR-42 with selective androgen receptor modulators (SARM) with effective anabolic effect on muscle, might potential enhance the efficacy against cancer cachexia. Non-steroidal, orally available, SARMs have recently been developed that demonstrate full agonist in anabolic tissues like skeletal muscle and bone but are devoid of the side effects associated with 5a-reductase and aromatase substrates. Clinically, GTX-024, has shown promising gains in fat free mass in cancer patients[1] but failed to demonstrate a clear functional benefit in a cachectic cancer population[2]. Here, we reported that GTx-024 alone cannot prevent cancer induced cachexia, however, once GTx-024 co-treated with relative low dose of AR-42, it can protect cancer cachexia induced losses of body weight, skeletal muscle weight, and adipose tissue in C-26 tumor bearing mice model. Consistent with the protective effect on muscle mass, handgrip dynamometry showed that AR-42 was able to preserve muscle function in combination treatment group comparing to vehicle control. We also found this synergistic effect was not GTx-024 dependent; both DHT and TFM-4AS-1 can repeat the protective effect co-treated with AR-42 in C-26 bearing mice model, but failed to achieve the protection when treated alone. Together, these results support further evaluation of combined AR-42 and SARMs administration as a potential treatment against cancer induced cachexia.
Ching-Shih Chen (Committee Member)
Denis Guttridge (Committee Member)
Karl Werbovetz (Committee Member)
Mitch Phelps (Committee Member)
154 p.

Recommended Citations

Citations

  • Tseng, Y.-C. (2017). Application of Histone Deacetylase Inhibitor AR-42 in the Treatment of Cancer-induced Cachexia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1500375156831813

    APA Style (7th edition)

  • Tseng, Yu-Chou. Application of Histone Deacetylase Inhibitor AR-42 in the Treatment of Cancer-induced Cachexia. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1500375156831813.

    MLA Style (8th edition)

  • Tseng, Yu-Chou. "Application of Histone Deacetylase Inhibitor AR-42 in the Treatment of Cancer-induced Cachexia." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1500375156831813

    Chicago Manual of Style (17th edition)