Novel molecular biomarkers of cancer therapy-induced cardiotoxicity in adult population: a scoping review.

AIM: Cancer treatments are associated with cardiotoxic events that predispose to cardiac pathology and compromise the survival of patients, making necessary the identification of new molecular biomarkers to detect cardiotoxicity. This scoping review aims to identify the available evidence on novel molecular biomarkers associated with cardiotoxicity in the adult population undergoing cancer therapy. METHODS AND RESULTS: The databases Medline, Web of Science, Scopus, and Embase were screened for the identification of published studies until 23 August 2020, searching for novel molecular biomarkers reported in cancer therapy-related cardiac dysfunction in adult patients. A total of 42 studies that met the eligibility criteria were included. Fourteen studies reported 44 new protein biomarkers, 18 studies reported 57 new single nucleotide polymorphism biomarkers, and 11 studies reported 171 new gene expression profiles associated with cardiotoxicity. Data were extracted for 272 novel molecular biomarkers reported and evaluated in 7084 cancer patients, of which only 13 were identified in more than one study (MPO, sST2, GDF-15, TGF-B1, rs1056892, rs1883112, rs4673, rs13058338, rs1695, miR-1, miR-25-3p, miR-34a-5p, and miR-423-5p), showing values for area under the curve > 0.73 (range 0.74-0.85), odds ratio 0.26-7.17, and hazard ratio 1.28-1.80. CONCLUSIONS: Multiple studies presented a significant number of novel molecular biomarkers as promising predictors for risk assessment of cardiac dysfunction related to cancer therapy, but the characteristics of the studies carried out and the determinations applied do not allow suggesting the clinical use of these molecular biomarkers in the assessment of cancer therapy-induced cardiotoxicity.

Functional and transcriptomic characterization of cisplatin-resistant AGS and MKN-28 gastric cancer cell lines.

Gastric cancer (GC) is a significant cancer-related cause of death worldwide. The most used chemotherapeutic regimen in GC is based on platinum drugs such as cisplatin (CDDP). However, CDDP resistance reduces advanced GC survival. In vitro drug-resistant cell model would help in the understanding of molecular mechanisms underlying this drug-resistance phenomenon. The aim of this study was to characterize new models of CDDP-resistant GC cell lines (AGS R-CDDP and MKN-28 R-CDDP) obtained through a stepwise increasing drug doses method, in order to understand the molecular mechanisms underlying chemoresistance as well as identify new therapeutic targets for the treatment of GC. Cell viability assays, cell death assays and the expression of resistance molecular markers confirmed that AGS R-CDDP and MKN-28 R-CDDP are reliable CDDP-resistant models. RNA-seq and bioinformatics analyses identified a total of 189 DEGs, including 178 up-regulated genes and 11 down-regulated genes, associated mainly to molecular functions involved in CDDP-resistance. DEGs were enriched in 23 metabolic pathways, among which the most enriched was the inflammation mediated by chemokine and cytokine signaling pathway. Finally, the higher mRNA expression of SERPINA1, BTC and CCL5, three up-regulated DEGs associated to CDDP resistance found by RNA-seq analysis was confirmed. In summary, this study showed that AGS R-CDDP and MKN-28 R-CDDP are reliable models of CDDP resistance because resemble many of resistant phenotype in GC, being also useful to assess potential therapeutic targets for the treatment of gastric cancers resistant to CDDP. In addition, we identified several DEGs associated with molecular functions such as binding, catalytic activity, transcription regulator activity and transporter activity, as well as signaling pathways associated with inflammation process, which could be involved in the development of CDDP resistance in GC. Further studies are necessary to clarify the role of inflammatory processes in GC resistant to CDDP and these models could be useful for these purposes.