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Mehrdad Roghani - One of the best experts on this subject based on the ideXlab platform.
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pelargonidin improves memory deficit in amyloid β25 35 rat model of alzheimer s disease by inhibition of glial activation cholinesterase and oxidative stress
Biomedicine & Pharmacotherapy, 2016Co-Authors: Hamid Sohanaki, Tourandokht Baluchnejadmojarad, Farnaz Nikbakht, Mehrdad RoghaniAbstract:Abstract Alzheimer’s disease (AD) is a multifactorial disorder with devastating outcomes and few mostly palliative available therapeutic strategies. Pelargonidin (Pel), an anthocyanin compound, is an Estrogen Receptor Agonist with lower side effects versus Estrogen. This study examined neuroprotective effect of Pel on intrahippocampal amyloid β25-35 (Aβ) rat model of AD. Rats were divided into groups of sham, Aβ, and Pel-pretreated Aβ (10 mg/kg; p.o.). Animals underwent Morris water maze (MWM) test in addition to measurement of hippocampal oxidative stress, acetylcholinesterase (AChE) activity, glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS). Pel pretreatment of Aβ group significantly improved escape latency and distance swum in MWM versus Aβ group and attenuated hippocampal malondialdehyde (MDA) and increased catalase activity with no significant change of nitrite. Meanwhile, Pel improved hippocampal AChE activity and lowered GFAP level with no significant change of iNOS. Our results suggest that Pel could improve Aβ25-35-induced memory deficit through mitigation of oxidative stress, cholinergic dysfunction, and astrocyte reaction.
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pelargonidin improves passive avoidance task performance in a rat amyloid beta25 35 model of alzheimer s disease via Estrogen Receptor independent pathways
Acta medica Iranica, 2016Co-Authors: Hamid Sohanaki, Tourandokht Baluchnejadmojarad, Farnaz Nikbakht, Mehrdad RoghaniAbstract:Alzheimer's disease (AD) is a disorder with multiple pathophysiological causes, destructive outcomes, and no available definitive cure. Pelargonidin (Pel), an anthocyanin derivative, is an Estrogen Receptor Agonist with little Estrogen side effects. This study was designed to assess Pel memory enhancing effects on the a rat Amyloid Beta25-35 (Aβ) intrahippocampal microinjections model of AD in the passive avoidance task performance paradigm and further evaluate the potential Estrogen Receptor role on the memory-evoking compound. Equally divided rats were assigned to 5 groups of sham, Aβ intrahippocampal microinjected, Pel pretreated (10 mg/kg; P.O), α Estrogen antAgonist intra-cerebrovascular (i.c.v.) microinjected, and β Estrogen antAgonist (i.c.v) microinjected animals. Intrahippocampal microinjections of Aβ were adopted to provoke AD model. Passive avoidance task test was also used to assess memory performance. Pel pretreatment prior to Aβ microinjections significantly improved step-through latency (P<0.001) in passive avoidance test. In α and β Estrogen, antAgonists received animals, passive avoidance task performance was not statistically changed (P=0.11 & P=0.41 respectively) compared to Pel pretreated and sham animals. Our results depicted that Pel improves Aβ induced memory dysfunction in passive avoidance test performance through Estrogen Receptor independently related pathways.
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Pelargonidin Improves Passive Avoidance Task Performance in a Rat Amyloid Beta25-35 Model of Alzheimer's Disease Via Estrogen Receptor Independent Pathways.
Acta medica Iranica, 2016Co-Authors: Hamid Sohanaki, Tourandokht Baluchnejadmojarad, Farnaz Nikbakht, Mehrdad RoghaniAbstract:Alzheimer's disease (AD) is a disorder with multiple pathophysiological causes, destructive outcomes, and no available definitive cure. Pelargonidin (Pel), an anthocyanin derivative, is an Estrogen Receptor Agonist with little Estrogen side effects. This study was designed to assess Pel memory enhancing effects on the a rat Amyloid Beta25-35 (Aβ) intrahippocampal microinjections model of AD in the passive avoidance task performance paradigm and further evaluate the potential Estrogen Receptor role on the memory-evoking compound. Equally divided rats were assigned to 5 groups of sham, Aβ intrahippocampal microinjected, Pel pretreated (10 mg/kg; P.O), α Estrogen antAgonist intra-cerebrovascular (i.c.v.) microinjected, and β Estrogen antAgonist (i.c.v) microinjected animals. Intrahippocampal microinjections of Aβ were adopted to provoke AD model. Passive avoidance task test was also used to assess memory performance. Pel pretreatment prior to Aβ microinjections significantly improved step-through latency (P
Barry S. Komm - One of the best experts on this subject based on the ideXlab platform.
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Selective Estrogen Receptor modulators and the combination therapy conjugated Estrogens/bazedoxifene: A review of effects on the breast
Post reproductive health, 2015Co-Authors: James H Pickar, Barry S. KommAbstract:Traditional menopausal hormone therapy containing Estrogens/progestin has been associated with an increased risk of breast cancer, and Estrogen exposure is known to promote growth and proliferation of a majority of breast cancers. Therefore, it is important for clinicians to consider the breast safety profile of any hormone-based therapy used in postmenopausal women. This review provides an overview of the breast safety and tolerability profiles of currently marketed selective Estrogen Receptor modulators, antiEstrogens, and the first tissue selective Estrogen complex combining conjugated Estrogens with the selective Estrogen Receptor modulator bazedoxifene in postmenopausal women. Selective Estrogen Receptor modulators and antiEstrogens act as Estrogen Receptor antAgonists in the breast. Tamoxifen, toremifene, and the selective Estrogen Receptor degrader fulvestrant are used to treat breast cancer, and tamoxifen and raloxifene protect against breast cancer in high-risk women. Postmenopausal women using selective Estrogen Receptor modulators for prevention or treatment of osteoporosis (raloxifene, bazedoxifene) can be reassured that these hormonal treatments do not adversely affect their risk of breast cancer and may, in the case of raloxifene, even be protective. There are limited data on breast cancer in women who use ospemifene for dyspareunia. Conjugated Estrogens/bazedoxifene use for up to two years did not increase mammographic breast density or breast pain/tenderness, and there was no evidence of an increased risk of breast cancer, suggesting that conjugated Estrogens/bazedoxifene has an improved breast safety profile compared with traditional menopausal hormone therapies. Future research will continue to focus on development of selective Estrogen Receptor modulators and selective Estrogen Receptor modulator combinations capable of achieving the ideal balance of Estrogen Receptor Agonist and antAgonist effects.
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selective Estrogen Receptor modulators and the combination therapy conjugated Estrogens bazedoxifene a review of effects on the breast
Post Reproductive Health: The Journal of The British Menopause Society, 2015Co-Authors: James H Pickar, Barry S. KommAbstract:Traditional menopausal hormone therapy containing Estrogens/progestin has been associated with an increased risk of breast cancer, and Estrogen exposure is known to promote growth and proliferation of a majority of breast cancers. Therefore, it is important for clinicians to consider the breast safety profile of any hormone-based therapy used in postmenopausal women. This review provides an overview of the breast safety and tolerability profiles of currently marketed selective Estrogen Receptor modulators, antiEstrogens, and the first tissue selective Estrogen complex combining conjugated Estrogens with the selective Estrogen Receptor modulator bazedoxifene in postmenopausal women. Selective Estrogen Receptor modulators and antiEstrogens act as Estrogen Receptor antAgonists in the breast. Tamoxifen, toremifene, and the selective Estrogen Receptor degrader fulvestrant are used to treat breast cancer, and tamoxifen and raloxifene protect against breast cancer in high-risk women. Postmenopausal women using selective Estrogen Receptor modulators for prevention or treatment of osteoporosis (raloxifene, bazedoxifene) can be reassured that these hormonal treatments do not adversely affect their risk of breast cancer and may, in the case of raloxifene, even be protective. There are limited data on breast cancer in women who use ospemifene for dyspareunia. Conjugated Estrogens/bazedoxifene use for up to two years did not increase mammographic breast density or breast pain/tenderness, and there was no evidence of an increased risk of breast cancer, suggesting that conjugated Estrogens/bazedoxifene has an improved breast safety profile compared with traditional menopausal hormone therapies. Future research will continue to focus on development of selective Estrogen Receptor modulators and selective Estrogen Receptor modulator combinations capable of achieving the ideal balance of Estrogen Receptor Agonist and antAgonist effects.
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development of conjugated Estrogens bazedoxifene the first tissue selective Estrogen complex tsec for management of menopausal hot flashes and postmenopausal bone loss
Steroids, 2014Co-Authors: Barry S. Komm, Sebastian Mirkin, Simon N JenkinsAbstract:Abstract Conjugated Estrogens (CE) combined with the selective Estrogen Receptor modulator (SERM) bazedoxifene (BZA) is a new option for alleviating menopausal symptoms and preventing postmenopausal bone loss. The rationale for developing the tissue selective Estrogen complex (TSEC) CE/BZA was to combine CE’s benefits with the SERM’s tissue-specific properties to offset Estrogenic stimulation of endometrial and breast tissue. TSECs provide a progestin-free alternative to traditional Estrogen–progestin therapy (EPT) in women with a uterus. Preclinical studies supported bazedoxifene as the SERM of choice and demonstrated that CE/BZA provided an optimal balance of Estrogen Receptor Agonist/antAgonist activity compared with other potential TSEC pairings. Initial clinical development of CE/BZA focused on determining the appropriate dose ratio that would demonstrate efficacy with minimal to no stimulation of the breast or endometrium. Clinical studies confirmed the efficacy of the selected doses for maintaining bone mass; relieving vasomotor symptoms, vulvar–vaginal atrophy, and dyspareunia; and improving sexual function in postmenopausal women. Reduction of hot flashes also translated into improved menopause-specific quality of life and sleep. Unlike EPT, the FDA-approved dose of CE 0.45 mg/BZA 20 mg does not cause a change in breast density or the endometrium, or increase breast pain compared with placebo. In clinical trials up to 2 years, CE 0.45 mg/BZA 20 mg has a favorable tolerability profile and rates of coronary heart disease, venous thromboembolism, and amenorrhea similar to placebo. Therefore, CE 0.45 mg/BZA 20 mg is an effective, well-tolerated alternative to EPT for menopausal symptom relief and osteoporosis prevention for postmenopausal women with a uterus.
Hamid Sohanaki - One of the best experts on this subject based on the ideXlab platform.
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pelargonidin improves memory deficit in amyloid β25 35 rat model of alzheimer s disease by inhibition of glial activation cholinesterase and oxidative stress
Biomedicine & Pharmacotherapy, 2016Co-Authors: Hamid Sohanaki, Tourandokht Baluchnejadmojarad, Farnaz Nikbakht, Mehrdad RoghaniAbstract:Abstract Alzheimer’s disease (AD) is a multifactorial disorder with devastating outcomes and few mostly palliative available therapeutic strategies. Pelargonidin (Pel), an anthocyanin compound, is an Estrogen Receptor Agonist with lower side effects versus Estrogen. This study examined neuroprotective effect of Pel on intrahippocampal amyloid β25-35 (Aβ) rat model of AD. Rats were divided into groups of sham, Aβ, and Pel-pretreated Aβ (10 mg/kg; p.o.). Animals underwent Morris water maze (MWM) test in addition to measurement of hippocampal oxidative stress, acetylcholinesterase (AChE) activity, glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS). Pel pretreatment of Aβ group significantly improved escape latency and distance swum in MWM versus Aβ group and attenuated hippocampal malondialdehyde (MDA) and increased catalase activity with no significant change of nitrite. Meanwhile, Pel improved hippocampal AChE activity and lowered GFAP level with no significant change of iNOS. Our results suggest that Pel could improve Aβ25-35-induced memory deficit through mitigation of oxidative stress, cholinergic dysfunction, and astrocyte reaction.
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pelargonidin improves passive avoidance task performance in a rat amyloid beta25 35 model of alzheimer s disease via Estrogen Receptor independent pathways
Acta medica Iranica, 2016Co-Authors: Hamid Sohanaki, Tourandokht Baluchnejadmojarad, Farnaz Nikbakht, Mehrdad RoghaniAbstract:Alzheimer's disease (AD) is a disorder with multiple pathophysiological causes, destructive outcomes, and no available definitive cure. Pelargonidin (Pel), an anthocyanin derivative, is an Estrogen Receptor Agonist with little Estrogen side effects. This study was designed to assess Pel memory enhancing effects on the a rat Amyloid Beta25-35 (Aβ) intrahippocampal microinjections model of AD in the passive avoidance task performance paradigm and further evaluate the potential Estrogen Receptor role on the memory-evoking compound. Equally divided rats were assigned to 5 groups of sham, Aβ intrahippocampal microinjected, Pel pretreated (10 mg/kg; P.O), α Estrogen antAgonist intra-cerebrovascular (i.c.v.) microinjected, and β Estrogen antAgonist (i.c.v) microinjected animals. Intrahippocampal microinjections of Aβ were adopted to provoke AD model. Passive avoidance task test was also used to assess memory performance. Pel pretreatment prior to Aβ microinjections significantly improved step-through latency (P<0.001) in passive avoidance test. In α and β Estrogen, antAgonists received animals, passive avoidance task performance was not statistically changed (P=0.11 & P=0.41 respectively) compared to Pel pretreated and sham animals. Our results depicted that Pel improves Aβ induced memory dysfunction in passive avoidance test performance through Estrogen Receptor independently related pathways.
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Pelargonidin Improves Passive Avoidance Task Performance in a Rat Amyloid Beta25-35 Model of Alzheimer's Disease Via Estrogen Receptor Independent Pathways.
Acta medica Iranica, 2016Co-Authors: Hamid Sohanaki, Tourandokht Baluchnejadmojarad, Farnaz Nikbakht, Mehrdad RoghaniAbstract:Alzheimer's disease (AD) is a disorder with multiple pathophysiological causes, destructive outcomes, and no available definitive cure. Pelargonidin (Pel), an anthocyanin derivative, is an Estrogen Receptor Agonist with little Estrogen side effects. This study was designed to assess Pel memory enhancing effects on the a rat Amyloid Beta25-35 (Aβ) intrahippocampal microinjections model of AD in the passive avoidance task performance paradigm and further evaluate the potential Estrogen Receptor role on the memory-evoking compound. Equally divided rats were assigned to 5 groups of sham, Aβ intrahippocampal microinjected, Pel pretreated (10 mg/kg; P.O), α Estrogen antAgonist intra-cerebrovascular (i.c.v.) microinjected, and β Estrogen antAgonist (i.c.v) microinjected animals. Intrahippocampal microinjections of Aβ were adopted to provoke AD model. Passive avoidance task test was also used to assess memory performance. Pel pretreatment prior to Aβ microinjections significantly improved step-through latency (P
John C. O'connor - One of the best experts on this subject based on the ideXlab platform.
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Ex vivo and in vitro testis and ovary explants: utility for identifying steroid biosynthesis inhibitors and comparison to a Tier I screening battery.
Toxicological Sciences, 1998Co-Authors: Stephanie S. Powlin, Jon C. Cook, Stephen Novak, John C. O'connorAbstract:Testis and ovary explants have been proposed asin vitroscreens for identifying potential inhibitors of steroid biosynthesis. The goals of the current study were to optimize the conditions of the two assays, to characterize these assays using several compounds with well-defined endocrine activity, and to compare the responses from the explant assays with anin vivomale battery currently undergoing validation using the Crl:CD BR rat in order to evaluate their utility as test systems for screening unknown compounds for possible steroid biosynthesis inhibition activity. There were two components to the testis/ovary assays:ex vivoandin vitro.Theex vivocomponent used testes/ovaries from animals dosed with the test compoundsin vivo,and thein vitrocomponent used testes/ovaries from control animals. For the testis assays, decapsulated testis explants (50 mg) were placed into glass scintillation vials, ±1.0 IU/ml hCG for 3 h in a shaking water bath (34°C). Following the incubation period, medium was removed, centrifuged, and frozen until assayed for hormone concentrations. A similar procedure was used for the ovary explant assay except that each ovary was incubated separately. The testis explants were evaluated using the following compounds: ketoconazole (KETO), a testosterone biosynthesis inhibitor; aminoglutethimide (AG) (onlyin vitro) and anastrozole (ANA), aromatase inhibitors; finasteride (FIN), a 5α-reductase inhibitor; 17β-estradiol (17β-E2), an Estrogen Receptor Agonist; flutamide (FLUT), an androgen Receptor antAgonist; ICI-182,780 (ICI), an Estrogen Receptor antAgonist; haloperidol (HALO), a D2Receptor antAgonist; and reserpine (RES), a dopamine depletor. In the ovary assay, AG (onlyin vitro), ANA, ICI, and HALO (onlyin vitro) were evaluated. Addition of fetal calf serum to the medium allowed measurement of estradiol (E2) in the testis assay, but production was not inhibited by ANA or AG. In the ovary explant assay, only AG was identified as inhibiting E2 productionin vitro.Hence, both the testis and ovary explant assays appear to have limited utility for detecting aromatase inhibitors. Screening of these nine diverse endocrine-active compounds resulted in all of them being identified as altering the endocrine system when assessed byex vivoandin vitrotestis explants. Using only thein vitroassessment with the criteria of steroid biosynthesis inhibition, four of nine compounds were correctly identified in the testis explant assay (17β-E2, KETO, FLUT, and HALO). The predictability of both thein vitroandex vivoovary assay was 50%, suggesting a 50% false positive or negative rate with unknown compounds. However, of the seven compounds assessed to date (17β-E2, ICI, ANA, KETO, FLUT, HALO, and RES), all were correctly identified using anin vivomale battery, which also has the capability to detect other endocrine activities. Therefore, the testis and ovary explant assay would not be necessary if one were using anin vivomale battery, since this screen would identify steroid biosynthesis inhibitors and would also identify several other endocrine activities. Because of the difficulties in assessing cytotoxicity and the high false positive/negative rates, the ovary and testis explant assays are not useful as routine screening procedures for detecting steroid biosynthesis inhibitors; however, they may have utility in confirmingin vivofindings.
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Sensitivity of a Tier I Screening Battery Compared to an in Utero Exposure for Detecting the Estrogen Receptor Agonist 17β-Estradiol
Toxicological sciences : an official journal of the Society of Toxicology, 1998Co-Authors: John C. O'connor, Jon C. Cook, Steven R. Frame, Lisa B. Biegel, Leonard G. DavisAbstract:A Tier I screening battery for detecting endocrine active compounds (EACs) has been evaluated for its ability to identify 17 beta-estradiol, a pure Estrogen Receptor Agonist. In addition, the responses obtained with the Tier I battery were compared to the responses obtained from F1 generation rats from a 90-day/one-generation reproduction study with 17 beta-estradiol in order to characterize the sensitivity of the Tier I battery against the sensitivity of an in utero exposure for detecting EACs. The Tier I battery incorporates two short-term in vivo tests (5-day ovariectomized female battery; 15-day intact male battery) and an in vitro yeast transactivation system (YTS) for identifying compounds that alter endocrine homeostasis. The Tier I female battery consists of traditional uterotrophic endpoints coupled with biochemical and hormonal endpoints. It is designed to identify compounds that are Estrogenic/antiEstrogenic or modulate dopamine levels. The Tier I male battery consists of organ weights coupled with microscopic evaluations and a comprehensive hormonal assessment. It is designed to identify compounds that have the potential to act as Agonists or antAgonists to the Estrogen, androgen, progesterone, or dopamine Receptor; steroid biosynthesis inhibitors (aromatase, 5 alpha-reductase, and testosterone biosynthesis); or compounds that alter thyroid function. The YTS is designed to identify compounds that bind to steroid hormone Receptors (Estrogen, androgen, and progesterone) and activate gene transcription. The profile generated for 17 beta-estradiol was characteristic of the responses expected with a pure Estrogen Receptor Agonist. In the female battery, responses to 17 beta-estradiol included increases in uterine fluid imbibition, uterine weight, estrus conversion, uterine stromal cell proliferation, uterine epithelial cell height, uterine progesterone Receptor content, serum prolactin and estradiol levels, and decreases in uterine Estrogen Receptor content and follicle stimulating hormone and luteinizing hormone levels. In the male battery, responses to 17 beta-estradiol included decreases in absolute testis and epididymides weights, decreases in relative weights for androgen-dependent tissues (prostate, seminal vesicles, and accessory sex gland unit), hormonal alterations (decreased serum testosterone, dihydrotestosterone, and LH and increased serum prolactin levels), and microscopic alterations of the testis and epididymides. In the YTS for the Estrogen Receptor, 17 beta-estradiol had an EC50 value of 7.2 x 10(-9) M, while DHT and progesterone had little cross-activation. The androgen and progesterone Receptor systems were less selective in that 17 beta-estradiol activated these systems within 3 orders of magnitude of the primary ligand. In the 90-day/one-generation reproduction study, responses to dietary administration of 17 beta-estradiol included alterations in organ weights, developmental landmarks, and hormonal levels. Comparison of the responses obtained with our Tier I battery and an in utero exposure demonstrates that the Tier I screening battery is as sensitive as an in utero exposure for detecting 17 beta-estradiol-induced alterations in hormonal homeostasis.
John S Davis - One of the best experts on this subject based on the ideXlab platform.
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the g protein coupled Estrogen Receptor Agonist g 1 suppresses proliferation of ovarian cancer cells by blocking tubulin polymerization
Cell Death and Disease, 2013Co-Authors: Cheng Wang, Xiangmin Lv, Chunbo He, My Tsai, John S DavisAbstract:The G-protein-coupled Estrogen Receptor 1 (GPER) has recently been reported to mediate the non-genomic action of Estrogen in different types of cells and tissues. G-1 (1-[4-(6-bromobenzo[1,3] dioxol-5yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone) was developed as a potent and selective Agonist for GPER. G-1 has been shown to induce the expression of genes and activate pathways that facilitate cancer cell proliferation by activating GPER. Here we demonstrate that G-1 has an anticancer potential with a mechanism similar to vinca alkaloids, the commonly used chemotherapy drugs. We found that G-1 blocks tubulin polymerization and thereby interrupts microtubule assembly in ovarian cancer cells leading to the arrest of cell cycle in the prophase of mitosis and the suppression of ovarian cancer cell proliferation. G-1 treatment also induces apoptosis of ovarian cancer cells. The ability of G-1 to target microtubules to suppress ovarian cancer cell proliferation makes it a promising candidate drug for treatment of ovarian cancer.
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the putative g protein coupled Estrogen Receptor Agonist g 1 suppresses proliferation of ovarian and breast cancer cells in a gper independent manner
American Journal of Translational Research, 2012Co-Authors: Cheng Wang, Chao Jiang, John S DavisAbstract:G-protein coupled Estrogen Receptor 1 (GPER) plays an important role in mediating Estrogen action in many different tissues under both physiological and pathological conditions. G-1 (1-[4-(6-bromobenzo[1,3]dioxol-5yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl]-ethanone) has been developed as a selective GPER Agonist to distinguish Estrogen actions mediated by GPER from those mediated by classic Estrogen Receptors. In the present study, we surprisingly found that G-1 suppressed proliferation and induced apoptosis of KGN cells (a human ovarian granulosa cell tumor cell line), actions that were not blocked by a selective GPER antAgonist G15 or siRNA knockdown of GPER. G-1 also suppressed proliferation and induced cell apoptosis in GPER-negative HEK-293 cells and MDA-MB 231 breast cancer cells. Our results demonstrate that G-1 suppresses proliferation of ovarian and breast cancer cells in a GPER-independent manner. G-1 may be a candidate for the development of drugs against ovarian and breast cancer.