Combination Therapy with Bisoprolol and Tissue Protective Molecule ARA 284 Is Cardio-Protective and Improves Survival in Experimental Cancer Cachexia

Background: Cancer cachexia is a serious condition during the last stages of the disease, which is characterized by the loss of muscle and fat mass in patients with cancer. There are no effective treatments for cancer cachexia, and new treatment interventions are urgently needed. We have previously demonstrated that 5 mg/kg/day bisoprolol and 1.7 µg/kg/day ARA 284, a small non-erythropoietic tissue protective peptide, separately have positive effects in a rat model of cancer cachexia. Methods: We investigated the compound effects of both bisoprolol and ARA 284 by targeting multiple pathways in the Yoshida hepatoma rat model of cancer cachexia. Rats were randomly allocated to one of the following treatment groups: bisoprolol (5 mg/kg/day), ARA 284 (1.7 µg/kg/day), a 25% combination (1.25 mg/kg/day bisoprolol + 0.425 µg/kg/day ARA 284), a 75% combination (3.75 mg/kg/day bisoprolol + 1.275 µg/kg/day ARA 284), or placebo. Results: The combination of 3.75 mg/kg/day bisoprolol and 1.275 µg/kg/day ARA 284 showed the strongest overall effects compared with the respective effective monotherapies, respectively, or placebo across multiple endpoints, including body weight, lean mass, food intake, spontaneous activity, and cardiac function in a rat model of cancer cachexia (p < 0.01, respectively). Furthermore, this combination therapy had the strongest effects on survival against the placebo (hazard ratio 0.08, 95% confidence interval 0.04 to 0.17, p < 0.001). Conclusions: Our findings show that the combination of bisoprolol and ARA 284 is beneficial in a hepatoma cachexia model and may provide greater overall effects than either monotherapy alone.