salicylates and Endometrial-Neoplasms

Endometrial cancer (EC) is the fourth most common malignancy in women in developed countries. The prognosis of EC is extremely poor, and it is an important factor that contributes to the death of patients. Therefore, studying EC pathogenesis and therapeutic targets, and exploring effective drugs are the primary tasks to improve the prognosis of EC. In the present study, we aimed to explore the function of ginkgolic acid (GA) in EC cell apoptosis and autophagy through PI3K/Akt/mTOR signal pathway in vitro and in vivo. Firstly, MTT assay and clone formation assay were employed to analyze the Ishikawa and HEC-1-B cell viabilities and proliferation after treatment with GA. The results showed that GA inhibited endometrial cancer cell survival. Flow cytometry assay and western blot assay were applied to examine the apoptosis and apoptosis related protein Bcl-2, Bax, Cleaved caspase-3 expression levels of Ishikawa and HEC-1-B cells after treatment with GA. Next, we applied western blot assay to analyze the autophagy associated proteins LC3I, LC3II, p62 and Beclin-1 in GA treated Ishikawa and HEC-1-B cells. We found that GA promoted apoptosis and induced autophagy of endometrial cancer cells. Meanwhile, western blot assay was also used to determine the expression levels of the PI3K/Akt/mTOR signal pathway related protein and the results revealed that GA inhibited the activity of PI3K/Akt/mTOR pathway. Finally, we found that GA inhibited tumor growth in vivo through immunohistochemistry assay. In conclusion, GA induces apoptosis and autophagy of EC cells via inhibiting PI3K/Akt/mTOR pathway in vivo and

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Cell Line, Tumor; Cell Survival; Endometrial Neoplasms; Female; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Salicylates; Signal Transduction; TOR Serine-Threonine Kinases

Type 2 endometrial carcinoma (EC) is a poorly differentiated EC. Unlike type 1 EC, which responds to hormonal treatment (progestins), type 2 EC is refractory to hormonal treatment because of its low expression of active estrogen and progesterone receptors (ER, PR). The aim of this study was to develop a novel drug combination designed to treat these aggressive type 2 EC tumors without surgery and with fertility potential preserved. We examined the effects of combined treatment with the progestin medroxyprogesterone acetate (MPA) and the Ras inhibitor S-farnesylthiosalicylic acid (FTS; Salirasib). Because FTS can induce cell differentiation in tumor cells, we examined whether FTS could induce re-differentiation of type 2 EC cells, thereby sensitizing them to MPA. We found that FTS reduced Ras-GTP, phospho- Akt, and phospho-ERK, and that these reductions all correlated with a decrease in ERα phosphorylation. Combined treatment with FTS and MPA induced stronger reduction in USPC1 type 2 EC cell numbers than the reduction induced by either drug alone. MPA caused ERα degradation. Death of the cells was caused by MPA but not by FTS. The phosphorylated ERα induces gene transcription manifested by enhanced cell proliferation and survival. The combination of FTS and MPA, by reducing the mRNA expression of ERα-mediated genes (i.e. PR, c-fos and ps2/TFF1), inhibited tumor growth and enhanced the death of type 2 EC cells. These promising results might herald a novel treatment for the highly aggressive, incurable type 2 endometrial carcinoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Cell Growth Processes; Cell Line, Tumor; Down-Regulation; Endometrial Neoplasms; Estrogen Receptor alpha; Estrogen Receptor beta; Farnesol; Female; Gene Expression Regulation, Neoplastic; Humans; Medroxyprogesterone Acetate; Phosphorylation; ras Proteins; RNA, Messenger; Salicylates; Transcription, Genetic

An effective, unprecedented replacement of the prototypical phenolic 'A-ring' of estrogens with an oxime and a hydroxy-moiety of the salicylaldoxime derivative 3,4-diphenyl-substituted (1a) opened the way to study structure-activity relationships of a new class of estrogen receptor (ER)-ligands. Herein, we present a study of the ER binding properties and transcriptional activities of analogues of 3,4-diphenylsalicylaldoxime (1a). The introduction of p-OH and p-OMe groups on the phenyl substituents of 1a, as in compounds 1b-g, results in unique structure-activity profiles. The preparation of the hetero-disubstituted compounds (1b-e) was accomplished by a sequential introduction of different 3- and 4-aryl groups, obtained by exploiting the different reactivity of the bromine versus chlorine substituents on the precursor, 2-bromo-3-chloronitrobenzene (5), in the palladium-catalyzed cross-coupling reactions. The results of the biological tests show that the introduction of one hydroxy-group on the 3-phenyl substituent of the lead compound 1a improved the binding affinity on ERbeta (1c), whereas the introduction of the same group on the 4-phenyl substituent of 1a gave a compound (1e) with better affinity properties on ERalpha. The introduction of two hydroxyl groups in the para-position of both phenyl substituents of 1a, as in 1g, lowered the binding on both receptor subtypes. In transcription assays, the ERalpha agonist character of this class of ligands is enhanced by the presence of a p-hydroxy or p-methoxy in the 'distal' phenyl ring, whereas substitution on the other phenyl ring does not substantially modify the partial agonist character of 1a. Thus, results from the binding and transcription assays illustrate that this class of ER ligands has a distinct structure-activity profile on the two ER subtypes, being potent nearly full agonists on ERalpha and weak, partial antagonists on ERbeta.

Topics: Cloning, Molecular; Dose-Response Relationship, Drug; Endometrial Neoplasms; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Humans; Indicators and Reagents; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Oximes; Receptors, Estrogen; Salicylates; Selective Estrogen Receptor Modulators; Transcription, Genetic; Tumor Cells, Cultured