wedelolactone and Ovarian-Neoplasms

Altered glucose-6-phosphate dehydrogenase (G6PD) status is influential in many cellular pathophysiological processes and diseases, making G6PD a potential target for cancer therapy. However, the available G6PD inhibitors are very limited and restricted. Here we developed a reducing equivalent nicotinamide adenine dinucleotide phosphate (NADPH) absorption photometry assay based on enzyme kinetics to characterize G6PD activity. In this way, we performed a high-throughput screening (HTS) to an in house library. And then we identified compound named Wedelolactone inhibiting G6PD strongly in a non-competitive, reversible way. In addition, we did the surface Plasmon Resonance (SPR) assay and indicated the K

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Coumarins; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Female; Glucosephosphate Dehydrogenase; High-Throughput Screening Assays; Humans; NADP; Ovarian Neoplasms; Oxidation-Reduction; Protein Binding; Structure-Activity Relationship; Surface Plasmon Resonance

Identification and development of new drug candidates to be used singly or in combination therapy is critical in anticancer research. In recent years, accumulating evidence encouraged us to investigate the anti-proliferative effects of a small and emerging phytochemical Wedelolactone (WDL) in estrogen-dependent and independent multiple gynecological tumor models.. The aim of this study was to investigate the growth inhibitory effect of WDL on estrogen- dependent and independent gynecological cell lines and to explore its inhibitory potential towards key targets through in silico study.. Cytotoxicity of WDL was investigated in human breast and ovarian cancer cell lines (MCF-7 and SKOV3) through 3-(4,5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) reduction assay. Epigallocatechingallate (EGCG) was used as reference natural compound while cisplatin was taken as a standard clinical agent. Both WDL and EGCG in combination with cisplatin were also evaluated for their combined growth inhibitory potential in MCF-7 cells. WDL was also evaluated in silico against key factors including braf kinases, CDPK, ERα, aromatase, topoisomerase II and dihydrofolate reductase (DHFR) playing pivotal roles in driving multiple tumors.. The IC50 value of WDL was 25.77 ± 4.82 μM and 33.64 ± 1.45 μM in MCF-7 and SKOV-3 respectively. The binding energy order was as follows; WDL: DHFR >Braf kinases > CDPK; aromatase > topoisomerase II> ERα > NFkB > alkaline phosphatase; EGCG dihydrofolatereductase (DHFR) > aromatase >CDPK > topoisomerase II > braf kinases > alkaline phosphatase > CDPK > ERα > NFkB.. We identified WDL as a cytotoxic agent in breast and ovarian tumor models with the potential to inhibit multiple targets in the oncogenic pathway including estrogen receptor ERα, as depicted through its in silico study. Based on our own research findings and from literature evidence, we conclude that further research should be encouraged to investigate different aspects of wedelolactone as an additional agent to be combined with antiestrogen/endocrine therapy.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Computer Simulation; Coumarins; Female; Humans; MCF-7 Cells; Ovarian Neoplasms

Estrogen and estrogen receptor (ER)-mediated signaling pathways play important roles in the etiology and progression of human breast, endometrial, and ovarian cancers. Attenuating ER activities by natural products and their derivatives is a relatively practical strategy to control and reduce breast, endometrial, and ovarian cancer risk. Here, we found 3-butoxy-1,8,9-trihydroxy-6H-benzofuro[3,2-c]benzopyran-6-one (BTB), a new derivative of wedelolactone, could effectively inhibit the 17-estradiol (E2)-induced ER transactivation and suppress the growth of breast cancer as well as endometrial and ovarian cancer cells. Our results indicate that 2.5 μM BTB effectively suppresses ER-positive, but not ER-negative, breast, endometrial, and ovarian cancer cells. Furthermore, our data indicate that BTB can modulate ER transactivation and suppress the expression of E2-mediated ER target genes (Cyclin D1, E2F1, and TERT) in the ER-positive MCF-7, Ishikawa, and SKOV-3 cells. Importantly, this BTB mediated inhibition of ER activity is selective since BTB does not suppress the activities of other nuclear receptors, including glucocorticoid receptor and progesterone receptor, suggesting that BTB functions as a selective ER signaling inhibitor with the potential to treat breast, endometrial, and ovarian cancers.

Topics: Breast Neoplasms; Cell Proliferation; Coumarins; Cyclin D1; Endometrial Neoplasms; Estradiol; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Ovarian Neoplasms; Signal Transduction