Abstract
The moderate-to-high in vitro cytotoxicity against ovarian A2780 (IC50 = 4.7–14.4 μM), prostate LNCaP (IC50 = 18.7–30.8 μM) and prostate PC-3 (IC50 = 17.6–42.3 μM) human cancer cell lines of the platinum(II) cyclobutane-1,1'-dicarboxylato complexes [Pt(cbdc)(naza)2] (1–6; cbdc = cyclobutane-1,1'-dicarboxylate(2-); naza = halogeno-substituted 7-azaindoles), derived from the anticancer metallodrug carboplatin, are reported. The complexes containing the chloro- and bromo-substituted 7-azaindoles (1, 2, and 4–6) showed a significantly higher (p < 0.05) cytotoxicity against A2780 cell line as compared to cisplatin used as a reference drug. Addition of the non-toxic concentration (5.0 μM) of L-buthionine sulfoximine (L-BSO, an effective inhibitor of γ-glutamylcysteine synthase) markedly increases the in vitro cytotoxicity of the selected complex 3 against A2780 cancer cell line by a factor of about 4.4. The cytotoxicity against A2780 and LNCaP cells, as well as the DNA platination, were effectively enhanced by UVA light irradiation (λmax = 365 nm) of the complexes, with the highest phototoxicity determined for compound 3, resulting in a 4-fold decline in the A2780 cells viability from 25.1% to 6.1%. The 1H NMR and ESI-MS experiments suggested that the complexes did not interact with glutathione as well as their ability to interact with guanosine monophosphate. The studies also confirmed UVA light induced the formation of the cis [Pt(H2O)2(cbdc`)(naza)] intermediate, where cbdc` represents monodentate-coordinated cbdc ligand, which is thought to be responsible for the enhanced cytotoxicity. This is further supported by the results of transcription mapping experiments showing that the studied complexes preferentially form the bifunctional adducts with DNA under UVA irradiation, in contrast to the formation of the less effective monofunctional adducts in dark.
Highlights
The well-known story of platinum-based anticancer metallotherapeutics have slowly reached their second half-century, the application, development and research is still one of the leading branches of bioinorganic chemistry [1,2,3]
In vitro cytotoxicity of the complexes 1– 6, cisplatin and carboplatin was tested by an MTT assay against ovarian carcinoma A2780 (ECACC No 93112519), prostate carcinoma LNCaP (ECACC No 89110211) and prostate carcinoma PC-3 (ECACC No 90112714) human cancer cells obtained from European Collection of Cell Cultures (ECACC), as described in our previous works [11,13]
In comparison to the recently studied dichlorido complexes (IC50 = 1.8–2.6 μM against A2780 and 1.5–3.8 μM against LNCaP cells [11]) with analogous N-donor ligands, the complexes studied in this work (1–6) are less effective against the mentioned human cancer cell lines
Summary
The well-known story of platinum-based anticancer metallotherapeutics have slowly reached their second half-century, the application, development and research is still one of the leading branches of bioinorganic chemistry [1,2,3]. In the case of dichlorido complexes, considerably high in vitro cytotoxicity (with IC50 values up to 0.6 μM) was found against various human cancer cell lines (ovarian A2780, breast MCF7, osteosarcoma HOS, lung A549, cervical HeLa, malignant melanoma G361 and prostate LNCaP) These cisplatin analogues complexes successfully overcame an acquired resistance to cancer cells (ovarian carcinoma model) and effectively reduced the tumor tissues volume during the in vivo experiments on mice (L1210 lymphocytic leukemia model), while showing less serious negative side-effects on the healthy tissues as compared with cisplatin [13]. The above-mentioned positive findings, regarding the in vitro and in vivo anticancer activities of platinum(II) complexes bearing 7-azaindole monodentate ligands, motivated us to study the carboplatin analogues involving the mentioned N-donor ligands (Fig 1), their cytotoxicity on selected human cancer cell lines and mechanisms of their action under normal conditions and upon UVA light irradiation, using the set of advanced analytical and biological methods
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