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Molecular mechanisms underlying synergistic anticancer effects of spliceosome inhibitor combined with cisplatin
Author(s) -
Anufrieva Ksenia,
Shender Victoria,
Shnaider Polina,
Ivanova Olga,
Boichenko Veronika,
Baymukhanova Zhanat,
Lagarkova Maria,
Arapidi Georgij
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.05322
Subject(s) - spliceosome , cancer research , cisplatin , dna damage , chronic lymphocytic leukemia , cell cycle , apoptosis , cancer cell , in vivo , cancer , biology , chemistry , microbiology and biotechnology , leukemia , chemotherapy , rna splicing , dna , immunology , biochemistry , genetics , rna , gene
Recently, several splicing inhibitors (Spliceostatin A, Pladienolide B, H3B‐8800) have been proposed as effective and promising chemotherapeutic agents. These drugs have been shown to be effective in treating various types of cancer, such as chronic lymphocytic leukemia, breast adenocarcinoma, prostate cancer, ovarian adenocarcinoma and colorectal adenocarcinoma (Bonnal, Vigevani, and Valcárcel 2012; Webb, Joyner, and Potter 2013; Sciarrillo et al. 2019; Jiménez‐Vacas et al. 2019). These molecules effectively eliminate cancer cells both in vivo and in vitro, but multiple side effects have been identified in phase I clinical trials due to the compounds' high toxicity (Eskens et al. 2013). We believe that optimal scheme of combined chemotherapy can reduce the concentration of splicing inhibitors and reduce their toxicity. Based on bioinformatic analysis, we have demonstrated that DNA‐damaging drugs lead to a decrease in the number of spliceosomal proteins in the cell (Anufrieva, 2018). According to our results, decreased abundance of spliceosomal proteins can contribute to cancer cell survival after therapy. A decrease in the presence of spliceosomal proteins in the cell triggers the cell cycle arrest and serves as signal about the DNA damage. We have shown that spliceosome inhibitor (Pladienolide B) can suppress such response to DNA damaging chemotherapy. Based on survival analysis and apoptosis assessment, we found that Pladienolide B significantly increases the sensitivity of cancer cells to Cisplatin.Using flow cytometry and immunofluorescence assay for DNA repair marker (phospho‐ATM) we showed that sequential treatment with spliceosome inhibitor and DNA‐damaging agent leads to therapeutic synergy in vitro due to reduced DNA repair efficiency. Further, we performed proteomic profiling of ovarian cancer cells SKOV3 after sequential treatment of Pladienolide B and Cisplatin. It was shown that the action of the two drugs resulted in a massive reduction in the abundance of proteins involved in DNA repair as well as proteins involved in TP53 activation. Apparently, the spliceosome inhibitor Pladienolide B leads to the activation of compensatory mechanisms in the cell resulting in increased expression of genes involved in mRNA splicing. Thus, we showed that sequential action of Pladienolide B and Cisplatin reduces the efficiency of DNA repair in the cell. This synergistic effect could allow to reduce the therapeutic doses of these drugs and avoid the side effects found in patients during therapy with splicing inhibitor drugs.