Adhip P N Majumdar
Tumor recurrence and/or metastasis, a common phenomenon in all malignancies, is observed in nearly 50% of patients with colorectal cancer (CRC). This could in part be due to enrichment of chemotherapy-resistant cancer stem cells (CSCs), accompanied by dysfunction of the gut microbiota (dysbiosis), resulting in alterations in microbial metabolites and byproducts in the gut and tumor, some of which may be responsible for the recurrence of CRC. Thus, development of preventive/therapeutic strategies that simultaneously targets the growth potential of CSCs as well as impact the tumor promoting microbiome population should be effective in reducing the risk of relapse and metastasis. We have examined the effectiveness of the combination of ETOcurcumin (ETO-Cur; curcumin complexed with essential turmeric oil) and tocotrienol-rich fraction (TRF) of a palm oil in inhibiting the growth of severe combined immunodeficiency (SCID) mice xenograft of chemo-resistant (CR) colon cancer cells and whether this inhibition could be attributed to alterations in gut and tumor microbiome and their metabolites. Indeed, feeding (oral gavage) of ETO-Cur (5 mg/kg) together with TRF (2 mg/kg) or the vehicle (control) in SCID mice, initiated after about 20 days of inoculation of CR colon cancer cells in SCID mice, which continued for 45 days resulted in a marked inhibition of growth of colon tumor. At 40- and 45 days, differences in tumor growth between the two groups were statistically significant. This inhibition of growth was not only associated with a significant down-regulation of β-catenin and TNF-α in the tumor but also with alterations in gut microbiota. The latter is evidenced by an overlap 340 bacterial species between the control and ETO-Cur/TFR-treated SCID mice and 216 and 120 species being different in ETO-Cur and TRF treated mice, respectively. A marked increase in antiinflammatory Lactobacillaceae and Bifidobacteriaceae and reduction in pro-inflammatory Akkermansia spp. was observed in feces from ETO-Cur/TRF treated SCID mice, compared to controls. Although the precise nature of bacterial participation in inhibition of growth of colon tumor remains unresolved, we have observed a significant reduction in the expression of 7-α-dehydroxylase in fecal and tumor cells from ETO-Cur + TRF treated SCID mice, compared to controls. This suggests that the conversion of bile acids to carcinogens catalyzed by 7-α-dehydroxylase is suppressed by ETO-Cur/TRF treatment. Since secondary bile acids, specifically deoxycholic (DCA) and lithocholic (LCA) acid are known for their co-carcinogenic activity and to induce CSCs in the colon, we postulate that reduction of luminal DCA and/or LCA by ETO-Cur/TRF may have contributed to the prevention of growth of colon tumors.
Note: This work is partly presented at 4th Edition of World Congress on Cancer Research, Survivorship and Management Conference, October 08-09, 2018 held at Moscow, Russia