Molecular Mechanisms of Anticancer Activity of N-Glycosides of Indolocarbazoles LCS-1208 and LCS-1269.

Autor: Zenkov RG; N. N. Blokhin Russian Cancer Research Center, 24 Kashirskoe Shosse, 115478 Moscow, Russia., Vlasova OA; N. N. Blokhin Russian Cancer Research Center, 24 Kashirskoe Shosse, 115478 Moscow, Russia., Maksimova VP; N. N. Blokhin Russian Cancer Research Center, 24 Kashirskoe Shosse, 115478 Moscow, Russia., Fetisov TI; N. N. Blokhin Russian Cancer Research Center, 24 Kashirskoe Shosse, 115478 Moscow, Russia., Karpechenko NY; N. N. Blokhin Russian Cancer Research Center, 24 Kashirskoe Shosse, 115478 Moscow, Russia., Ektova LV; N. N. Blokhin Russian Cancer Research Center, 24 Kashirskoe Shosse, 115478 Moscow, Russia., Eremina VA; N. N. Blokhin Russian Cancer Research Center, 24 Kashirskoe Shosse, 115478 Moscow, Russia., Popova VG; N. N. Blokhin Russian Cancer Research Center, 24 Kashirskoe Shosse, 115478 Moscow, Russia.; Faculty of Biotechnology and Industrial Ecology, Mendeleev University of Chemical Technology of Russia, 9 Miusskaya Ploshchad, 125047 Moscow, Russia., Usalka OG; N. N. Blokhin Russian Cancer Research Center, 24 Kashirskoe Shosse, 115478 Moscow, Russia.; International School 'Medicine of the Future', I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya St., 119991 Moscow, Russia., Lesovaya EA; N. N. Blokhin Russian Cancer Research Center, 24 Kashirskoe Shosse, 115478 Moscow, Russia.; Department of Oncology, I.P. Pavlov Ryazan State Medical University, 9 Vysokovoltnaya St., 390026 Ryazan, Russia., Belitsky GA; N. N. Blokhin Russian Cancer Research Center, 24 Kashirskoe Shosse, 115478 Moscow, Russia., Yakubovskaya MG; N. N. Blokhin Russian Cancer Research Center, 24 Kashirskoe Shosse, 115478 Moscow, Russia., Kirsanov KI; N. N. Blokhin Russian Cancer Research Center, 24 Kashirskoe Shosse, 115478 Moscow, Russia.; Institute of Medicine, RUDN University, 6 Miklukho-Maklaya St., 117198 Moscow, Russia.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2021 Dec 02; Vol. 26 (23). Date of Electronic Publication: 2021 Dec 02.
DOI: 10.3390/molecules26237329
Abstrakt: Novel indolocarbazole derivatives named LCS were synthesized by our research group. Two of them were selected as the most active anticancer agents in vivo. We studied the mechanisms of anticancer activity in accordance with the previously described effects of indolocarbazoles. Cytotoxicity was estimated by MTT assay. We analyzed LCS-DNA interactions by circular dichroism in cholesteric liquid crystals and fluorescent indicator displacement assay. The effect on the activity of topoisomerases I and II was studied by DNA relaxation assay. Expression of interferon signaling target genes was estimated by RT-PCR. Chromatin remodeling was analyzed-the effect on histone H1 localization and reactivation of epigenetically silenced genes. LCS-induced change in the expression of a wide gene set was counted by means of PCR array. Our study revealed the cytotoxic activity of the compounds against 11 cancer cell lines and it was higher than in immortalized cells. Both compounds bind DNA; binding constants were estimated-LCS-1208 demonstrated higher affinity than LCS-1269; it was shown that LCS-1208 intercalates into DNA that is typical for rebeccamycin derivatives. LCS-1208 also inhibits topoisomerases I and IIα. Being a strong intercalator and topoisomerase inhibitor, LCS-1208 upregulates the expression of interferon-induced genes. In view of LCSs binding to DNA we analyzed their influence on chromatin stability and revealed that LCS-1269 displaces histone H1. Our analysis of chromatin remodeling also included a wide set of epigenetic experiments in which LCS-1269 demonstrated complex epigenetic activity. Finally, we revealed that the antitumor effect of the compounds is based not only on binding to DNA and chromatin remodeling but also on alternative mechanisms. Both compounds induce expression changes in genes involved in neoplastic transformation and target genes of the signaling pathways in cancer cells. Despite of being structurally similar, each compound has unique biological activities. The effects of LCS-1208 are associated with intercalation. The mechanisms of LCS-1269 include influence on higher levels such as chromatin remodeling and epigenetic effects.
Databáze: MEDLINE
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