Cisplatin and oxaliplatin are Pt(II) anticancer agents that are used to treat several cancers, usually in combination with other drugs. Their efficacy is diminished by dose-limiting peripheral neuropa Show more
Cisplatin and oxaliplatin are Pt(II) anticancer agents that are used to treat several cancers, usually in combination with other drugs. Their efficacy is diminished by dose-limiting peripheral neuropathy (PN) that affects ∼70% of patients. PN is caused by selective accumulation of the platinum drugs in the dorsal root ganglia (DRG), which overexpress transporters for cisplatin and oxaliplatin. To date, no drug is recommended for the prevention of PN. We report that Pt(IV) prodrugs of cisplatin or oxaliplatin do not induce neuropathic pain in mice, likely due to the lower accumulation of platinum in the DRG compared with Pt(II) drugs. Moreover, the multitargeting prodrug that combines cisplatin with paclitaxel, both strong inducers of PN, efficiently inhibited tumor growth in vivo without inducing neuropathic pain. The high antitumor efficacy of Pt(IV) prodrugs and their micellar counterparts and the low level of neuropathic pain associated with them make them ideal candidates for clinical use in cancer therapy. Show less
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence Show more
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health. Show less