Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy

Abstract

The malignant energetic demands are satisfied through glycolysis, glutaminolysis and de novo synthesis of fatty acids, while the host curses with a state of catabolism and systemic inflammation. The concurrent inhibition of both, tumor anabolism and host catabolism, and their effect upon tumor growth and whole animal metabolism, have not been evaluated. We aimed to evaluate in colon cancer cells a combination of six agents directed to block the tumor anabolism (orlistat + lonidamine + DON) and the host catabolism (growth hormone + insulin + indomethacin). Treatment reduced cellular viability, clonogenic capacity and cell cycle progression. These effects were associated with decreased glycolysis and oxidative phosphorylation, leading to a quiescent energetic phenotype, and with an aberrant transcriptomic landscape showing dysregulation in multiple metabolic pathways. The in vivo evaluation revealed a significant tumor volume inhibition, without damage to normal tissues. The six-drug combination preserved lean tissue and decreased fat loss, while the energy expenditure got decreased. Finally, a reduction in gene expression associated with thermogenesis was observed. Our findings demonstrate that the simultaneous use of this six-drug combination has anticancer effects by inducing a quiescent energetic phenotype of cultured cancer cells. Besides, the treatment is well-tolerated in mice and reduces whole animal energetic expenditure and fat loss.

Efeito da suplementação de glutamina em pacientes oncológicos

“…As células intestinais utilizam preferencialmente ácidos graxos de cadeia curta (AGCCs) como fonte de energia, formados pela degradação bacteriana da fibra alimentar no conteúdo fecal do cólon (ARADA et al, 2019). A glutamina pode ser utilizada de forma eficiente no cólon sem causar efeitos colaterais no seu processo de digestão e absorção, promovendo aumento da capacidade absortiva do epitélio intestinal em animais irradiados, melhorando a utilização de nutrientes e preservando a massa muscular dos indivíduos (Achamrah et al;2017). Compreender os mecanismos reguladores do metabolismo de aminoácidos em tecidos tumorais e tecidos do organismo hospedeiro é de suma importância para avaliar elementos terapêuticos que melhoram efetivamente a tumorigênese ou a qualidade de vida de pacientes com câncer.…”

Cancer Cachexia: Underlying Mechanisms and Potential Therapeutic Interventions

“…Parallel findings underscore the ability of moderate-intensity treadmill running to counteract the deleterious effects of IL-6-induced mitochondrial remodeling and proteolysis even amidst high systemic IL-6 levels [285]. Translating these insights to human exercise protocols, the American College of Sports Medicine (ACSM) recommends that cancer patients should participate in at least 150 min of moderate or 75 min of vigorous exercise each week [286].…”

Cancer cachexia: A scoping review on non-pharmacological interventions

“… 4 It includes “objective” components (i.e., inadequate food intake, weight loss, inactivity, loss of muscle mass and metabolic derangements, inducing catabolism) and “subjective” components (i.e., anorexia, early satiety, taste alterations, chronic nausea, distress, fatigue and loss of concentration). 2 , 5 …”