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  • br Materials and methods br Results br Discussion

    2022-06-20


    Materials and methods
    Results
    Discussion
    Conclusion Pharmacophore modeling was applied to explore new probable Glo-I inhibitors. Ninety two pharmacophoric models were generated representing diverse types of interaction between co-crystallized ligands and corresponding binding site. The generated pharmacophores were assessed using QSAR analysis followed by ROC evaluation. The uppermost ranked pharmacophore model, QSAR-selected model; Hypo(3VW9), was selected and used to screen the NCI library for novel chemical scaffolds. NCI compounds were docked using Libdock to assess the binding site interactions to facilitate capturing several low micromolar inhibitors. The predicted toxicity of active hits indicates that the compounds are drug-like with low incidence of toxicity.
    Conflict of interest
    Acknowledgments The authors thank the National Cancer Institute for supporting us with NCI samples. We also thank the deanship of Scientific Research at the Zarqa University with grant number 5-2016 and the deanship of scientific research at Jordan University of science and Technology for their generous funds with grant number 20170308.
    Introduction Endometrial cancer (EC) is the most common genital tract malignancy in developed countries [[1], [2], [3], [4]]. EC has been divided into type I (estrogen-dependent) and type II (estrogen-independent), and progestin has been used as the main treatment for patients with type I EC who want to reserve their fertility and patients with advanced or recurrent EC [5]. Traditional progestin treatment of EC requires a long duration and high dose; accordingly, this often leads to progestin resistance. Efforts have been done in the past few years to reveal the molecular mechanism underlying progestin resistance. Akt-PRB (progestin Go 6983 B) and Nrf2-survivin both are the signaling pathway which cause progestin resistance, our previous study as well as other’s results also demonstrated that PI3K-Akt pathway involves in progestin resistance [[6], [7], [8]]. Despite great progress has been obtained in the past decades regarding EC but the 5-year survival rate has not been potently improved. Recently, metformin was reported to improve the prognosis of multiple cancers including endometrial cancer. However, the underlying mechanism has not been fully explored. Metformin, the first line medication for type II diabetes and also applied for treatment of obesity and PCOS (polycystic ovarian syndrome) [9]. Epidemic research shows that the adoption of metformin reduced the risk of cancer occurrence and cancer related deaths with type II diabetes, which indicates that metformin is related to cancer therapy [10]. The combination of metformin with progestin reversed progestin resistant endometrial hyperplasia and the combination of metformin with medroxyprogesterone acetate inhibited atypical hyperplasia and EC from relapsing [11,12]. Similarly, the metformin have the potential to inhibitate the cancer cell proliferation in atypical endometrial hyperplasia and endometrial endometrioid adenocarcinoma [13]. Nowadays, metformin is regarded as ancillary drug for cancer therapy but the accurate mechanism of it has not yet been demonstrated clearly. Previous study suggested that GLOI is a target gene of metformin [5]. GLOI is a part of glyoxalase system, which contributes to progestin resistance in endometrial cancer [5]. It is ubiquitously expressed in mammalian animal. As a part of glyoxalase system, GLOI detoxifies methylglyoxal (MG) which has been reported endow antitumor activity in various cancers [14,15]. Besides, elevated GLOI expression is responsible for cancer cell proliferation and chemotherapeutic resistance [14]. Accumulating evidence suggests that metformin could suppress cellular growth and enhance drugs sensitivity to cancer by down regulation of GLOI expression. However, the detailed molecular mechanism has not been clarified. In our previous study, we found that metformin down regulated Ten-eleven translocation 1 (TET1) in EC cell lines, which leads to increased chemotherapy sensitivity that means metformin enhance the sensitivity of progestin in EC cell lines through TET1 [16]. TET1 is an important epigenetic modulator associated with endometrial cancer [16]. TET1 is one of the main components of the ten-eleven-translocation 5-methylcytosine dioxygenase family and catalyzes the conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). 5-hmC is a modified cytosine base. 5-hmC facilitates gene expression and it is a critical epigenetic marker of DNA hydroxymethylation. Hypothetically, this modification happens in GLOI gene and plays a critical role in GLOI-mediated progestin resistance.