Diosgenin promotes antitumor immunity and PD-1 antibody efficacy against melanoma by regulating intestinal microbiota

Abstract

Diosgenin, a natural steroidal saponin, can exert antitumor effect by regulating immune function and improving intestinal microbiota. The response to anti-PD-1 immunotherapy is associated with intestinal microbiota and effector T cells in tumor microenvironment. We hypothesize that the modulation of diosgenin on intestinal microbiota can facilitate antitumor immunity and the therapeutic efficacy of PD-1 antibody. In melanoma-bearing C57BL/6 mice, we observed that the anti-melanoma effect of diosgenin relied more on antitumor immunity than direct tumor inhibition activity evidenced by obvious CD4+/CD8+ T-cell infiltration and IFN-γ expression in tumor tissues, and it could improve the compositions of intestinal microbiota. Antibiotics impaired the therapeutic efficacy and immunity responses of diosgenin through disturbing intestinal microbiota, indicating the importance of intestinal microbiota in diosgenin’s in vivo antitumor activity. More importantly, the combined administration of PD-1 antibody with diosgenin aggravated the tumor necrosis and apoptosis by eliciting augmented T-cell responses. Taken together, diosgenin can be used as a microecological regulator to induce antitumor immunity and improve the efficacy of immune checkpoint antibody, making it more suitable for the treatment of malignant tumors.

Induction of G2/M Phase Arrest by Diosgenin via Activation of Chk1 Kinase and Cdc25C Regulatory Pathways to Promote Apoptosis in Human Breast Cancer Cells

“…In addition, diosgenin activates tumor cell autophagy and apoptosis by inhibiting the phosphorylation of phosphoinositide 3-kinase, Akt, and the mammalian target of rapamycin, thereby decreasing signaling through this pathway [31]. Furthermore, diosgenin can improve intestinal microbiota, which may increase immune functions to enhance the therapeutic efficacy of the checkpoint protein, PD-1, when treating melanoma [32]. Our results demonstrated that diosgenin induced time-and concentration-dependent inhibition of MCF-7 and Hs578T cell proliferation.…”

Clinical update on head and neck cancer: molecular biology and ongoing challenges

“…The momentous discovery that certain proteins act as “immune checkpoints” by regulating the T-cell response has spurred efforts to develop treatments to reverse this effect and restore anti-tumour immune responses 138,139 . In normal circumstances proteins including programmed death protein (PD-1), its ligand (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), function to prevent autoimmunity 140,141 .…”

Effects of Dioscorea polystachya 'yam gruel' on the cognitive function of diabetic rats with focal cerebral ischemia-reperfusion injury via the gut-brain axis

“…Previous studies have found that 'yam gruel' can increase the content of Bifidobacterium in the intestinal tract, regulate oxidative stress, relieve inflammatory response and reduce fasting blood glucose (FBG) levels in patients with diabetes (Pang et al, 2017). Studies in animal models of cognitive dysfunction have further revealed that the active components of yam regulate the composition of gut microbiota and improve memory dysfunction (Dong et al, 2018;Tohda et al, 2017). A considerable number of studies have shown that gut probiotics affect the regulation of cognitive function due to two-way communication channels between the gut and the brain, referred to as the 'gut-brain axis' (Hamidi et al, 2019;Martin et al, 2018).…”