RESUMEN
Introduction: The Cuban population is genetically diverse, and information on the prevalence of genetic variants is still limited. As complex admixture processes have occurred, we hypothesized that the frequency of pharmacogenetic variants and drug responses may vary within the country. The aims of the study were to describe the frequency distribution of 43 single-nucleotide variants (SNVs) from 25 genes of pharmacogenetic interest within the Cuba population and in relation to other populations, while taking into consideration some descriptive variables such as place of birth and skin color. Materials and Methods: SNVs were analyzed in 357 unrelated healthy Cuban volunteers. Genotype, allele frequencies, and ancestry proportions were determined, and the pairwise fixation index (FST ) was evaluated. Results: Hardy-Weinberg equilibrium (HWE) deviations in six loci (rs11572103, rs2740574, rs776746, rs3025039, rs861539, and rs1762429) were identified. Minor allele frequencies (MAFs) ranged from 0.00 to 0.15 for variants in genes encoding xenobiotic metabolizing enzymes. They also ranged from 0.01 to 0.21 for variants in DNA repair, growth factors, methyltransferase, and methyl-binding proteins, while they ranged from 0.04 to 0.27 for variants in the O-6-methylguanine-DNA methyltransferase enzyme. Moderate genetic divergence was observed upon comparison to Africans (FST = 0.071 and SD 0.079), with 19 markers exhibiting moderate-to-large genetic differentiation. The average European, African, and Amerindian ancestry proportions were 67.8%, 27.2%, and 5.3%, respectively. Ancestry proportions differed by skin color and birthplace for both African and European components, with the exception of the European component, which showed no significant difference between individuals from Western and Eastern regions. Meanwhile, the statistical significance varied in comparisons by skin color and birthplace within the Amerindian component. Low genetic divergence was observed across geographical regions. We identified 12 variants showing moderate-to-large differentiation between White/Black individuals. Conclusion: Altogether, our results may support national strategies for the introduction of pharmacogenetic tools in clinical practice, contributing to the development of precision medicine in Cuba.
RESUMEN
Marine plants have become an inexhaustible reservoir of new phytopharmaceuticals for cancer treatment. We demonstrate in vitro/in vivo antitumor efficacy of a standardized polyphenol extract from the marine angiosperm Thalassia testudinum (TTE) in colon tumor cell lines (RKO, SW480, and CT26) and a syngeneic allograft murine colorectal cancer model. MTT assays revealed a dose-dependent decrease of cell viability of RKO, CT26, and SW480 cells upon TTE treatment with IC50 values of, respectively, 175, 115, and 60 µg/mL. Furthermore, TTE significantly prevented basal and bFGF-induced angiogenesis in the chicken chorioallantoic membrane angiogenesis assay. In addition, TTE suppressed bFGF-induced migration of endothelial cells in a wound closure assay. Finally, TTE treatment abrogated CT26 colorectal cancer growth and increased overall organism survival in a syngeneic murine allograft model. Corresponding transcriptome profiling and pathway analysis allowed for the identification of the mechanism of action for the antitumor effects of TTE. In line with our in vitro/in vivo results, TTE treatment triggers ATF4-P53-NFκB specific gene expression and autophagy stress pathways. This results in suppression of colon cancer cell growth, cell motility, and angiogenesis pathways in vitro and in addition promotes antitumor immunogenic cell death in vivo.