The mechanisms of action of prenylated xanthones against breast, colon, and lung cancers, and their potential application against drug resistance

Cancers such as breast, colon, and lung cancers are among the leading causes of death with alarming increases in the number of new diagnoses and mortality rates. The non-specific toxicity limits current standard chemotherapeutic drugs, leading to severe and long-lasting side effects. New chemotherapeutic agents are urgently needed to address this worrying issue. A potential candidate to overcome this issue is xanthone, a natural compound that has been widely investigated for its promising cytotoxic activity. Specifically, prenylated xanthones exhibit good cytotoxicity against cancer cells with structure–activity relationship studies establishing prenyl moieties as the vital substituents in cellular internalization and binding interactions with molecular targets. A combination of in vitro, in vivo, and in silico approaches showed that xanthones exhibited various actions against breast, colon, and lung cancers, ranging from apoptosis, autophagy, cell cycle arrest, and modulation of key signaling pathways such as PI3K/Akt and MAPK. Prenylated xanthones could overcome drug resistance alone or combined with chemotherapeutic agents. The latter issue further corroborates their potential as anticancer drugs. α-Mangostin (2), γ-mangostin (3), and gambogenic acid (43) are considered lead molecules for developing antitumoral agents against breast, colon, and lung cancers. Other studies showed that prenylated xanthones, such as garcinone E (8), mangostanaxanthone IV (19), cowanin (20), mangosenone F (42), and many others, have potential anticancer activity. However, more comprehensive molecular investigations are required to establish their anticancer potential. Further studies are needed to elucidate prenylated xanthones’ pharmacokinetics and toxicity profiles to continue their progression through the drug development pipeline.

Graphical abstract