Petrova Maria, Vlahova Zlatina, Schröder Maria, Todorova Jordana, Tzintzarov Alexander, Gospodinov Anastas, Velkova Lyudmila, Kaynarov Dimitar, Dolashki Aleksandar, Dolashka Pavlina, Ugrinova Iva
Institute of Molecular Biology "Acad. Roumen Tsanev", Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bld. 21, 1113 Sofia, Bulgaria.
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bld. 9, 1113 Sofia, Bulgaria.
Pharmaceuticals (Basel). 2023 Jan 24;16(2):181. doi: 10.3390/ph16020181.
This study is the first report describing the promising antitumor activity of biologically active compounds isolated from the hemolymph of marine snail -a fraction with Mw between 50 and 100 kDa and two structural subunits (RvH1 and RvH2), tested on a panel of human breast cell lines-six lines of different molecular subtypes of breast cancer MDA-MB-231, MDA-MB-468, BT-474, BT-549, SK-BR-3, and MCF-7 and the non-cancerous MCF-10A. The fraction with Mw 50-100 kDa (HRv 50-100) showed good antitumor activity manifested by a significant decrease in cell viability, altered morphology, autophagy, and p53 activation in treated cancer cells. An apparent synergistic effect was observed for the combination of HRv 50-100 with cis-platin for all tested cell lines. The combination of HRv 50-100 with cisplatin and/or tamoxifen is three times more effective compared to treatment with classical chemotherapeutics alone. The main proteins in the active fraction, with Mw at ~50 kDa, ~65 kDa, ~100 kDa, were identified by MALDI-MS, MS/MS analyses, and bioinformatics. Homology was established with known proteins with antitumor potential detected in different mollusc species: peroxidase-like protein, glycoproteins Aplysianin A, L-amino acid oxidase (LAAO), and the functional unit with Mw 50 kDa of RvH. Our study reveals new perspectives for application of HRv 50-100 as an antitumor agent used alone or as a booster in combination with different chemotherapies.
本研究首次报道了从海洋蜗牛血淋巴中分离出的生物活性化合物具有有前景的抗肿瘤活性。该化合物为一个分子量在50至100 kDa之间的组分以及两个结构亚基(RvH1和RvH2),其在一组人乳腺癌细胞系上进行了测试,该细胞系包括六种不同分子亚型的乳腺癌细胞系——MDA-MB-231、MDA-MB-468、BT-474、BT-549、SK-BR-3和MCF-7,以及非癌性的MCF-10A。分子量为50至100 kDa的组分(HRv 50-100)显示出良好的抗肿瘤活性,表现为处理后的癌细胞活力显著降低、形态改变、自噬以及p53激活。对于所有测试细胞系,观察到HRv 50-100与顺铂联合使用具有明显的协同效应。HRv 50-100与顺铂和/或他莫昔芬联合使用的效果是单独使用传统化疗药物的三倍。通过基质辅助激光解吸电离质谱(MALDI-MS)、串联质谱(MS/MS)分析和生物信息学鉴定了活性组分中分子量约为50 kDa、65 kDa、100 kDa的主要蛋白质。与在不同软体动物物种中检测到的具有抗肿瘤潜力的已知蛋白质建立了同源性:过氧化物酶样蛋白、糖蛋白海兔毒素A、L-氨基酸氧化酶(LAAO)以及RvH分子量为50 kDa的功能单元。我们的研究揭示了将HRv 50-100单独用作抗肿瘤药物或与不同化疗药物联合用作增效剂的新应用前景。