Uncovering the pharmacological response of novel sesquiterpene derivatives that differentially alter gene expression and modulate the cell cycle in cancer cells.

Abstract

The present study aimed to assess the pharmacological anticancer profile of three natural and five synthetic sesquiterpenes developed by total chemical synthesis. To this end, their properties at the cellular and molecular level were evaluated in a panel of normal and cancer cell lines. The results obtained by performing cytotoxicity assays and gene expression analysis by reverse transcription-quantitative polymerase chain reaction showed that: i)Among the sesquiterpene derivatives analyzed, VDS58 exhibited a notable anticancer profile within attached (U-87 MG and MCF-7) and suspension (K562 and MEL-745) cancer cell cultures; however, U-87 MG cells were able to recover their proliferation capacity rapidly after 48h of exposure; ii)gene expression profiling of U-87 MG cells, in contrast to K562 cells, showed a transient induction of cyclin-dependent kinase inhibitor1A(CDKN1) expression; iii)the expression levels of transforming growth factorβ1(TGFB1) increased after 12h of exposure of U-87 MG cells to VDS58 and were maintained at this level throughout the treatment period; iv)in K562 cells exposed to VDS58, TGFB1 expression levels were upregulated for 48 h and decrease afterwards; and v)the re-addition of VDS58 in U-87 MG cultures pretreated with VDS58 resulted in a notable increase in the expression of caspases (CASP3 and CASP9), BCL2‑associated agonist of cell death (BAD), cyclinD1, CDK6, CDKN1, MYC proto-oncogene bHLH transcription factor(MYC), TGFB1 and tumor suppressor protein p53. This upregulation persisted only for 24h for the majority of genes, as afterwards, only the expression of TGFB1 and MYC was maintained at high levels. Through bioinformatic pathway analysis of RNA-Seq data of parental U-87 MG and K562 cells, substantial variation was reported in the expression profiles of the genes involved in the regulation of the cell cycle. This was associated with the differential pharmacological profiles observed in the same cells exposed to VDS58. Overall, the data presented in this study provide novel insights into the molecular mechanisms of action of sesquiterpene derivatives by dysregulating the expression levels of genes associated with the cell cycle of cancer cells.