Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.

Alpha-tocopherol (vitamin E) is a plant-derived dietary lipid that is essential for the health of most animals, including humans. Originally discovered as a fertility factor in rodents, the primary health-promoting properties of the vitamin in humans was shown to be protection of neuromuscular functions. Heritable vitamin E deficiency manifests in spinocerebellar ataxia that can be stabilized by timely supplementation with high-dose α-tocopherol. The molecular basis for α-tocopherol's biological activities has been attributed primarily to the vitamin's efficacy in preventing lipid peroxidation in membranes and lipoproteins, but the possibility that the vitamin possesses additional biological activities has been postulated and debated in the literature without conclusive resolution. We designed and synthesized a novel analog of α-tocopherol, 6-hydroxymethyl α-tocopherol (6-HMTC), which retains most of the vitamin's structural, physical, and biochemical properties, yet lacks measurable radical-trapping antioxidant activity. 6-HMTC bound to the tocopherol transfer protein with high (nanomolar) affinity, like that of the natural vitamin, attesting to the analog's preservation of structural integrity. Yet, 6-HMTC did not inhibit lipid peroxidation or associated ferroptotic cell death. Notably, 6-HMTC modulated the expression of some genes in a manner essentially identical to that exhibited by α-tocopherol. These findings support the notion that α-tocopherol modulates gene expression via an antioxidant-independent mechanism.

Hepatocellular carcinoma (HCC) is the most frequent primary hepatic malignancy and a leading cause of cancer-related death globally. HCC is associated with an indolent clinical presentation, resulting in frequent advanced stage diagnoses where surgical resection or transplant therapies are not an option and medical therapies are largely ineffective at improving survival. As such, there is a critical need to identify and enhance primary prevention strategies to mitigate HCC-related morbidity and mortality. Obesity is an independent risk factor for the onset and progression of HCC. Furthermore, obesity is a leading cause of nonalcoholic steatohepatitis (NASH), the fasting growing etiological factor of HCC. Herein, we review evolving clinical and mechanistic associations between obesity and hepatocarcinogenesis with an emphasis on the therapeutic efficacy of prevailing lifestyle/behavioral, medical, and surgical treatment strategies for weight reduction and NASH reversal.

Triple negative breast cancer (TNBC) is an aggressive and highly metastatic breast cancer subtype with limited treatment options. Obesity and insulin resistance are associated with a worse prognosis in those with TNBC. Moringa oleifera (moringa) is a tropical edible plant used for both food and medicinal purposes and found to have anti-obesity and anti-cancer effects in vitro and in preclinical models. The anti-cancer effects of moringa seed extract alone and in combination with chemotherapy were evaluated in immunocompromised female mice with diet-induced obesity bearing MDA-MB-231-derived xenograft tumors. Moringa supplementation protected against high-fat diet- and chemotherapy-induced increases in fasting glucose and improved insulin sensitivity. Moringa supplementation alone did not attenuate tumor growth relative to chemotherapy alone, and in combination worsened tumor progression. Moringa supplementation alone reduced angiogenesis, but this effect was abrogated in combination with chemotherapy. Moringa supplementation may be an effective strategy to improve metabolic health in mice with obesity and TNBC and reduce angiogenesis in tumors, but may have a negative interaction when used as a concurrent complementary therapy. Caution should be taken when considering the consumption of moringa seed extracts while receiving chemotherapy for breast cancer treatment. Further investigations of alternative timings of moringa therapy are warranted.

Purpose: Triple-negative breast cancer (TNBC) is an aggressive, highly metastatic malignancy with high recurrence rates. Hypoxia is a hallmark of the TNBC tumor microenvironment, which promotes tumor growth while impairing natural killer (NK) cell cytotoxic functions. Although acute exercise improves NK cell function under normoxic conditions, the effect of exercise on NK cell cytotoxic functions under hypoxic conditions mimicking O₂ tensions observed in solid tumors is unknown. Methods: The cytotoxic functions of resting and postexercise NK cells isolated from thirteen young inactive healthy women were assessed against breast cancer cells expressing different levels of hormone receptors (MCF-7 and MDA-MB-231) under normoxic and hypoxic conditions. Mitochondrial respiration and H₂O₂ efflux rates of the TNBC-activated NK cells were assessed via high-resolution respirometry. Results: Under hypoxia, postexercise NK cells exhibited greater killing of TNBC than resting NK cells. Further, postexercise NK cells were more likely to kill TNBC under hypoxia than normoxic conditions. In addition, mitochondrial respiration associated with oxidative (OXPHOS) capacity of TNBC-activated NK cells was greater in postexercise cells than resting cells under normoxia, but not under hypoxia. Finally, acute exercise was associated with reduced mitochondrial H₂O₂ efflux by NK cells in both conditions. Conclusions: Together, we present crucial interrelationships between hypoxia and exercise-induced changes in NK cell functions against TNBC cells. By modulating their mitochondrial bioenergetic functions, we postulate that acute exercise improves NK cell function under hypoxic conditions. Specifically, NK cell O₂ and H₂O₂ flow (pmol·s⁻¹·million NK cells⁻¹) changes in response to 30-min cycling suggest that exercise primes NK cell tumor killing by reducing mitochondrial oxidative stress and, thus, rescuing their function when exposed to harsh hypoxic environments as observed in the microenvironment of breast solid tumors.

Breast cancer is a common and deadly disease that causes tremendous physical, emotional, and financial burden on patients and society. Early-stage breast cancer and less aggressive subtypes have promising prognosis for patients, but in aggressive subtypes, and as cancers progress, treatment options and responses diminish, dramatically decreasing survival. Plants are nutritionally rich and biologically diverse organisms containing thousands of metabolites, some of which have chemopreventive, therapeutic, and sensitizing properties, providing a rich source for drug discovery. In this study we review the current landscape of breast cancer with a central focus on the potential role of phytochemicals for treatment, management, and disease prevention. We discuss the relevance of phytochemical targeting of mitochondria for improved anti-breast cancer efficacy. We highlight current applications of phytochemicals and derivative structures that display anti-cancer properties and modulate cancer mitochondria, while describing future applicability and identifying areas of promise.