Selective PI3Kγ inhibition attenuates chemotherapy-induced intestinal mucositis without compromising the anticancer properties of irinotecan

Abstract

Irinotecan-based anticancer therapy induces intestinal mucositis, increasing the risk of sepsis and patient death. The phosphoinositide 3-kinases (PI3K) are involved in cancer and inflammatory diseases, but their role in intestinal mucositis remains unknown. C57BL/6 male mice received vehicle (1 % DMSO, 10 ml/kg, p.o.), irinotecan alone or in combination with AS-605240 (a PI3Kγ inhibitor, 10 mg/kg, p.o.) or GSK2269557 (a PI3Kδ inhibitor, 3 mg/kg, p.o.). Histopathology, inflammatory markers, and diarrhea were assessed to evaluate mucositis. The antitumor effect was evaluated in mice inoculated with the Mc-38 colorectal cancer cell line. PI3Kγ inhibition attenuated irinotecan-induced intestinal injury, as evidenced by improved villus/crypt ratio. PI3Kγ inhibition also caused milder neutrophil accumulation, reduced expression of Tlr2, Tlr4, and Tlr9, and decreased levels of interleukin-1β and −6, as well as attenuated immunofluorescence for F4/80, a macrophage marker, and the regulatory T cell transcription factor FOXP3 (P < 0.05 vs. irinotecan). Additionally, AS-605240 prevented goblet cell loss and attenuated diarrhea. Moreover, PI3Kγ inhibition combined with irinotecan showed no synergistic anticancer effects. In contrast, PI3Kδ blockade did not prevent the development of mucositis but rather enhanced neutrophil accumulation in the intestine. PI3Kγ inhibition attenuates chemotherapy-associated intestinal mucositis without compromising the anticancer efficacy of irinotecan. However, selective inhibition of PI3Kδ exacerbates the inflammatory response and tissue damage.