A novel mechanism of the cachexia-promoting action of chemotherapy drugs fluorouracil and cisplatin

Chemotherapy often contributes to cachexia, a lethal comorbidity of cancer characterized by muscle wasting, resulting in poor therapeutic outcomes. Previous studies have shown that frequently prescribed chemotherapy medications fluorouracil and cisplatin are toxic to skeletal muscle directly, particularly at supratherapeutic doses without causing muscle catabolism. Here, we show that therapeutic doses of fluorouracil and cisplatin, indirectly stimulate muscle catabolism to increase muscle wasting by potentiating the cachexia-inducing capacity of cancer. At therapeutic doses that effectively reduce tumor volume, fluorouracil and cisplatin potentiate muscle wasting in KPC tumor-bearing mice by stimulating KPC cell release of EVs enriched with Hsp70 and Hsp90 that stimulate muscle catabolism. Fluorouracil and cisplatin stimulate EV release by upregulating Rab27a/b via activating NF-κB. In contrast, non-cachectic cancer cells respond to the drugs by releasing EVs not enriched with Hsp70/90. These data reveal a novel mechanism and potential therapeutic strategies for the cachexia-promoting action of fluorouracil and cisplatin.