Preclinical evidence for preventive and curative effects of resveratrol on xenograft cholangiocarcinogenesis

Resveratrol Promotes Self-digestion to Put Cancer to Sleep

“…Mice in the first group (that had not received any treatment for five weeks) served as controls, the mice in the second group were treated with 50 mg/kg RV in drinking water two weeks before tumor transplantation and for the next five weeks, and they served as the “preventive” group, and the mice in the third group started the RV treatment one week after tumor transplantation and served as the “curative” group. The results can be summarized as follows: (i) in controls, the tumors reached an average volume of 5.00 mm3 after 5 weeks in all the five mice, while in the “preventive” group, only three mice developed a tumor with an average volume of 0.15 mm3, and in the “curative” group the five mice developed a tumor with an average volume of 1.0 mm3; (ii) both in the “preventive” and “curative” groups, the infiltrate of CAFs and the presence of stromal IL-6 were drastically decreased; (iii) in the tumors from both the “preventive” and the “curative” groups, the autophagy markers microtubule-associated protein 1 light chain 3 (LC3) and BECLIN-1 were highly expressed [ 21 ].…”

“…In a separate study, we demonstrated that RV could keep ovarian cancer cells grown as 3D spheroids (a proxy of peritoneal metastatic colonies) in a dormant state even in the presence of IL-6, and this effect was due to the down-regulation of miR-1305 and concomitant re-expression of its target ARH-I (DIRAS3), which then rescued BECLIN-1-dependent autophagy [ 26 ]. By extracting the data from TCGA, we found that cholangiocarcinomas highly expressing BECN1 also showed high levels of DIRAS3 and CDKN1A mRNA, strongly suggesting a dormant state of the tumors [ 21 ]. This prompted us to check for the expression of ARH-I (DIRAS3) and autophagy and dormancy markers in the biopsies of the preclinical model of transplanted cholangiocarcinomas in nude mice described above.…”

“…As per the treatment endpoints, it is to be stressed that in our animal models treated with RV in drinking water, we obtained an effect not only in cancer cells (where markers of autophagy, apoptosis, cell cycle arrest and cell dormancy were induced) but also in the tumor microenvironment (where infiltration of CAFs and stromal IL-6 levels were decreased) [ 21 ]. In a separate study, we showed that RV also reduces angiogenesis and infiltration of immune-suppressive cells in the tumor microenvironment of transplanted lung cancer cells [ 19 ].…”