Currently, gastric cancer (GC) and gallbladder cancer (GBC) constitute important causes of human deaths related to cancer worldwide. In the last years, several researches are focused on the role of dietary compounds in preventing cancers. The consumption of fruits with high antioxidants, mainly anthocyanins, represents a good option to reduce the risk of chronic human diseases. Calafate (Berberis microphylla G. Forst.) berries, recognized by their remarkable antioxidant properties and high content of anthocyanins, appear as a new alternative to treat degenerative diseases of public interest. The present work was aimed to evaluate the impact of crude and anthocyanin-rich extracts from Calafate fruits on in vitro cell viability and migration capacity of gastric (AGC) and gallbladder (G415) human cancer cell lines, as related with their antioxidant properties. Crude and anthocyanin-rich extracts were obtained from fruits of Calafate grown under field conditions in the south of Chile. Antioxidants, phenols, anthocyanins, and anthocyanidins were determined. In vitro cell viability and migration of AGS and G415 human cancer cell lines at different concentrations of extracts (25-800 μg mL −1) were determined. Anthocyanin-rich extracts of Calafate berries showed comparable antioxidant activity (up to 1200 μg Trolox eq. g −1 DW), slightly lower total phenolic content (12%), but higher total anthocyanin content (25%) compared to the crude extract. The major anthocyanidin molecule detected in both extracts was delphinidin, followed by malvidin, and low concentrations of petunidin, cyanidin, and peonidin. As expected, all of these compounds were detected in higher levels in anthocyanin-rich extracts (up to 2-fold). Noteworthy, our study revealed that Calafate fruit extracts strongly decrease in vitro viability and migration capacity of gastric carcinoma (AGC model) and gallbladder carcinoma (G415 model) human cell lines; however, the anthocyanin-rich extract displayed higher inhibitory effects (up to 70%) compared to crude extracts. These findings allow suggesting that the in vitro antiproliferative potential of Calafate fruit extract is strongly related to the anthocyanin concentration, especially delphinidin.

Introduction: Ovarian cancer is one of the most lethal diseases in the female population worldwide. Indeed, the survival rate of ovarian cancer is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main chemotherapy treatment regimens is the use of platinum drugs, specifically carboplatin (CBDCA). Nevertheless, one of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways and tumor suppressors. In the last decade, lncRNAs have been identified as a new element responsible in the regulation of chemoresistant phenotype since they have been linked to multiple biological processes and acting in combination with other mechanism involved in chemoresistant. However, little is known about their role in carboplatin resistance in OC. This study seeks to characterize the effect of lncRNA expression on the chemoresistant phenotype and its correlation with the hyperactivation of drug efflux pumps. Materials and Methods: Ovarian cancer cell lines A2780-R-CBDCA, A2780-P, UCI-101, OVCAR3 and SKOV3 were used in this study. Chemosensitivity to carboplatin was measured by MTT Assay in 96-well plates after 24, 48 and 72h treatment for determinating IC50 values. Relative expression of MNX1-AS1 associated with CBDCA-resistant phenotype and efflux pumps were evaluated by qRT-PCR. Results: It was observed that A2780-R-CBDCA, SKOV3 and OVCAR3 cell lines presented the highest resistance indices in contrast to UCI-101 and A2780-P, which turned out to be highly sensitive to treatment with CBDCA. The relative expression of MNX1-AS1 was found elevated in those lines that presented higher levels of resistance to the drug, while in those more sensitive to treatment, the expression of MNX1-AS1 was found to be decreased. On the other hand, the expression levels of the ABCB1 and ABCC1 efflux pumps showed contradictory results in relation to their expression compared to the resistance index shown in each cell line. Mainly, it could be observed that ABCB1 presented a decreased expression in A2780-R-CBDCA, while ABCC1 was found to be increased in the same line. Conclusion: Our results indicate that the expression of MNX1-AS1 could contribute to the development or maintenance of a chemoresistant phenotype to platinum drugs. Meanwhile, the effect of the expression of MNX1-AS1 on the efflux pumps is not yet possible to relate as a modulator of its hyperactivation. However, their potential participation in this mechanism is not ruled out and new analyzes are necessary to rule out this possible relationship. Citation Format: Kurt Buchegger Mena, Tamara Viscarra Alvarez, Daniela León Garrido, Ramón Silva Pezoa, Carmen Ili Gangas, Sindy Cabarca Barreto, Marcela Berrios Flores, Jorge Sapunar Zenteno, Priscilla Brebi Mieville. MNX1-AS1 expression is positively correlates with expression of drug efflux pumps in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3897.

Introduction: Ovarian cancer (OC) is one of the most lethal diseases in the female population worldwide, being considered by 2020 the eighth most common type of cancer and the eighth cause of cancer death in that population. The most widely used chemotherapy treatment is based on the application of platinum based drugs, carboplatin (CBDCA) being one of the most common, in combination with taxanes and cisplatin. Unfortunately, a high percentage of the population relapses shortly after chemotherapy treatment, presenting a drug resistant phenotype. This phenotype reduces overall survival in patients with OC. In this context, various mechanisms have been investigated to understand and study these chemoresistant phenotypes. In the last decade, lncRNAs have been identified in multiple biological processes, including the development of drug-resistant phenotypes in malignant tumors, however, little is known about their role in carboplatin resistance in OC. This study seeks to characterize the effect of lncRNA expression on the chemoresistant phenotype and its potential molecular mechanism involved. Materials and Methods: Ovarian cancer cell lines corresponding to: A2780-R-CBDCA, A2780-P, UCI-101, OVCAR3 and SKOV3 were used. Drug susceptibility assays were performed using MTT. Relative expression was performed via RTqPCR. RNAseq was performed on a CBDCA resistance model in vitro using the Illumina HiSeq 4000 platform. Gene Ontology (GO) was analyzed using ClueGO. Gene set enrichment analysis (GSEA) was performed to define enriched biological pathways. Triplexator was used to predict the triplex forming oligonucleotides (TFO) and triplex target sites (TTS) that may be involved in the formation of RNA-DNA triplexes. Results: RNAseq analysis showed 156 differentially expressed protein coding genes (DEGs). The most enriched and deregulated signaling pathway was Wnt/β-catenin. In this context, several regulators of this pathway were found to be altered, including sFRP1, sFRP4, PCDHB6, CTNNA2, DACT1, PCDHB6, WNT3A, and CER1. In addition, 17 lncRNAs involved in CDBCA resistance were found to be deregulated. In this sense, MNX1-AS1 showed high levels of expression in CBDCA resistant cell lines. Interestingly, it has been shown that MNX1-AS1 has the ability to form a triplex with the PCDHB6 gene, which is a tumor suppressor gene and whose expression was found to be decreased in CBDCA resistant cell lines. Conclusions: Our results indicate that MNX1-AS1 expression could contribute to the modulation of platinum drug resistance through regulation of PCDHB6 expression via triplexes formation in OC. This finding could explain a new mechanism in CBDCA resistance in OC. Citation Format: Tamara Alejandra Viscarra Alvarez, Kurt Leopoldo Buchegger Mena, Daniela Inés León Garrido, Carmen Gloria Ili Gangas, Jorge Sapunar Zenteno, Marcela Berrios Flores, Ramón Silva Pezoa, Sindy Paola Cabarca Barreto, Priscilla Brebi Mieville. New potential mechanism of mnx1-as1 in the regulation of the carboplatin chemoresistant phenotype in ovarian cancer cell lines. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3895.