Determination of the migration effect and molecular docking of verteporfin in different subtypes of breast cancer cells
MOLECULAR MEDICINE REPORTS
Authors: Wei, Changran; Li, Xiangqi
Breast cancer is one of the most aggressive malignant tumors in women. According to the expression differences of estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 (HER-2) and cell proliferation antigen Ki-67, breast cancer can be divided into four molecular subtypes: Luminal A, Luminal B, HER-2 overexpression and Basal-like. Yes-associated protein (YAP), a downstream effector of the Hippo pathway, is overexpressed in human cancers and is associated with proliferation, apoptosis, migration, invasion and resistance to chemotherapy drugs in breast cancer cells. Verteporfin (VP) is used as a photosensitizer in the treatment of neovascular macular degeneration. VP is also identified as an inhibitor of YAP/TEA domain transcription factor (TEAD) interaction in the absence of light activation. However, detailed structural information about VP and YAP interactions is relatively scarce and VP research targeting YAP in different molecular subtypes of breast cancer cells is also rare. The aims of the present study were to structurally describe the VP binding site in the YAP crystal structure and to verify the non-photoreactive VP effect targeting YAP on the migration of different molecular subtypes of breast cancer cells. The crystal structure of VP and YAP was calculated by AutoDock 4.2 and the result was illustrated using PyMOL. The non-photoactivated VP effect on the migration of Luminal A MCF-7, Luminal B BT-474 and triple-negative breast cancer BT-549 breast cancer cells was evaluated by wound healing and Transwell migration experiments. Results from molecular docking experiments demonstrated that VP could interact through hydrogen bonds and hydrophobic interactions with important YAP residues involved in TEADs binding (Gln82, Val84, Met86 and Arg89). Migration experiments revealed that the non-photoinduced VP could inhibit the migration of different molecular subtypes of breast cancer cells. The results of the present study indicated that VP may be a novel repositioned drug for breast cancer treatment in the future.
A Pregnane Steroid as the Chiral Auxiliary in 1,3-Dipolar Azomethine Ylide's Cycloaddition: Asymmetric Synthesis and Anticancer Activity of Novel Hybrid Compounds
Authors: Kudryavtsev, Konstantin, V; Sokolov, Mikhail N.; Varpetyan, Eduard E.; Kirsanova, Anna A.; Fedotcheva, Nadezhda, I; Shimanovskii, Nikolai L.; Fedotcheva, Tatiana A.
Hybrid chiral molecules containing frameworks of a pregnane steroid and 5-arylpyrrolidine-2,4-dicarboxylate have been synthesized for the first time in a diastereomerically pure form. Chiral pregnane-based acrylate induced stereoselective formation of all-cistrisubstituted pyrrolidine moiety under cycloaddition with stabilized N-metalated azomethine ylides. beta-Dipeptidic fragment was built up at C-3 pregnane position using consequent acryloylation and stereoselective cycloaddition with stabilized N-metalated azomethine ylide. All novel hybrid molecules demonstrated micromolar cytotoxic activity against human cervical epithelioid cancer HeLa cell culture in native and estradiol-stimulated forms and breast carcinoma MCF-7 cell culture. The most of hybrid compounds are less toxic towards human skin fibroblasts HSF as compared with studied hormonal tumor cells.