Molecular Targets of Minor Cannabinoids in Breast Cancer: In Silico and In Vitro Studies.

Background: Breast cancer therapy has been facing remarkable changes. Classic treatments are now combined with other therapies to improve efficacy and surpass resistance. Indeed, the emergence of resistance demands the development of novel therapeutic approaches.

Alterations in the pro-resolving lipid mediator machinery within first trimester maternal tissue: Implications in decidualization and miscarriage risk.

A pivotal event in uterine receptivity and human reproduction is the differentiation of endometrial stromal cells into decidual cells, known as decidualization. Decidualization is interlinked with its inflammatory environment. Our study aimed to investigate the presence and role of pro-resolving lipid mediators in first trimester maternal tissue.

Cannabidivarin and cannabigerol induce unfolded protein response and angiogenesis dysregulation in placental trophoblast HTR-8/SVneo cells.

Cannabidivarin (CBDV) and cannabigerol (CBG) are minor phytocannabinoids from Cannabis sativa, whose health benefits have been reported. However, studies about the impact of these cannabinoids on fundamental cellular processes in placentation are scarce. Placental development involves physiological endoplasmic reticulum (ER) stress, however when exacerbated it can lead to altered angiogenesis and pregnancy disorders, such as intrauterine growth restriction and preeclampsia.

Understanding Hypertriglyceridemia: Integrating Genetic Insights.

Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute pancreatitis and cardiovascular diseases such as coronary artery disease. Its phenotype expression is widely heterogeneous and heavily influenced by conditions as obesity, alcohol consumption, or metabolic syndromes. Looking into the genetic underpinnings of hypertriglyceridemia, this review focuses on the genetic variants in , , , and triglyceride-regulating genes reportedly associated with abnormal genetic transcription and the translation of proteins participating in triglyceride-rich lipoprotein metabolism.

Effects of a combination of cannabidiol and delta-9-tetrahydrocannabinol on key biological functions of HTR-8/SVneo extravillous trophoblast cells.

In recent years, cannabis use has increased among pregnant women. In addition, the phytocannabinoids cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) alone or in combination are being used for therapeutical applications. THC and CBD are able to cross the placenta and a lot remains unknown concerning their impact on angiogenesis and extravillous trophoblasts' (EVTs) migration and invasion, which are essential processes for placentation.

Effects of Combining Genistein with Aromatase Inhibitors: Concerns Regarding Its Consumption during Breast Cancer Treatment.

Introduction: The third-generation of aromatase inhibitors (AIs)-Exemestane (Exe), Letrozole (Let), and Anastrozole (Ana)-is the main therapeutic approach applied for estrogen receptor-positive (ER+) breast cancer (BC), the most common neoplasm in women worldwide. Despite their success, the development of resistance limits their efficacy. Genistein (G), a phytoestrogen present in soybean, has promising anticancer properties in ER+ BC cells, even when combined with anticancer drugs.

Cannabidiol as a Promising Adjuvant Therapy for Estrogen Receptor-Positive Breast Tumors: Unveiling Its Benefits with Aromatase Inhibitors.

Background: Estrogen receptor-positive (ER) breast cancer is the most diagnosed subtype, with aromatase inhibitors (AIs) being one of the therapeutic drug types used in the clinic. However, endocrine resistance may develop after prolonged treatment, and different approaches, such as combining endocrine and targeted therapies, have been applied. Recently, we demonstrated that cannabidiol (CBD) induces anti-tumor actions in ER breast cancer cells by targeting aromatase and ERs.

The endocannabinoidome in human placenta: Possible contribution to the pathogenesis of preeclampsia.

Preeclampsia (PE) was first reported thousands of years ago, yet there is still a shortage of biomarkers to determine the severity and type of PE. The importance of the expanded endocannabinoid system, or endocannabinoidome (eCBome), has emerged recently in placental physiology and pathology, though the potential alterations of the eCBome in PE have not been fully explored. Analysis by qRT-PCR using placental samples of normotensive and PE women demonstrate for the first time the presence of ABHD4, GDE1, and DAGLβ in both normotensive and PE placental tissues.

Long-Term Tamoxifen Effects in the Cyclic Interaction of the Endocannabinoid and Endocrine System in the Rat Central Nervous System.

Steroid hormones can modulate the endocannabinoid system (ECS). Within the female reproductive tract, estrogen increases the expression of the cannabinoid receptors CB1 and CB2, and modifies the levels of anandamide (AEA), the major endocannabinoid, by altering the expression of both AEA synthesis (NAPE-PLD) and catabolic enzymes (FAAH). Here, we addressed the mechanisms involved in ECS fluctuations within the central nervous system and evaluated the effects of tamoxifen (TAM), a selective estrogen receptor modulator, in central AEA regulation.

An Exemestane Derivative, Oxymestane-D1, as a New Multi-Target Steroidal Aromatase Inhibitor for Estrogen Receptor-Positive (ER) Breast Cancer: Effects on Sensitive and Resistant Cell Lines.

Around 70-85% of all breast cancer (BC) cases are estrogen receptor-positive (ER). The third generation of aromatase inhibitors (AIs) is the first-line treatment option for these tumors. Despite their therapeutic success, they induce several side effects and resistance, which limits their efficacy.

Design, synthesis, biological activity evaluation and structure-activity relationships of new steroidal aromatase inhibitors. The case of C-ring and 7β substituted steroids.

In this work, new steroidal aromatase inhibitors (AIs) were designed, synthesized, and tested. In one approach, C-ring substituted steroids namely those functionalized at C-11 position with an α or β hydroxyl group or with a carbonyl group as well as C-9/C-11 steroidal olefins and epoxides were studied. It was found that the carbonyl group at C-11 is more beneficial for aromatase inhibition than the hydroxyl group, and that the C-ring epoxides were more potent than the C-ring olefins, leading to the discovery of a very strong AI, compound 7, with an IC of 0.

Bisphenols A, F, S and AF trigger apoptosis and/or endoplasmic reticulum stress in human endometrial stromal cells.

Disruption of non-differentiated endometrial stromal cells could have noxious consequences in female reproduction, impairing endometrial remodelling and implantation. Following the classification of bisphenol A (BPA) as an endocrine disrupting chemical, it started to be gradually withdrawn from the market, being substituted by structural analogues, whose effects in human health are not fully understood. This work used a telomerase-immortalized human endometrial stromal cell line (St-T1b) to study the effects of BPA and its three most commercialized structural analogues (ranked: bisphenols S, F and AF) on endometrial stromal cells to understand their effects on female reproductive function.

Cannabinoids in Breast Cancer: Differential Susceptibility According to Subtype.

Although cannabinoids have been used for centuries for diverse pathological conditions, recently, their clinical interest and application have emerged due to their diverse pharmacological properties. Indeed, it is well established that cannabinoids exert important actions on multiple sclerosis, epilepsy and pain relief. Regarding cancer, cannabinoids were first introduced to manage chemotherapy-related side effects, though several studies demonstrated that they could modulate the proliferation and death of different cancer cells, as well as angiogenesis, making them attractive agents for cancer treatment.

Effects of PI3K inhibition in AI-resistant breast cancer cell lines: autophagy, apoptosis, and cell cycle progression.

Introduction: Breast cancer is the leading cause of cancer death in women. The aromatase inhibitors (AIs), Anastrozole (Ana), Letrozole (Let), and Exemestane (Exe) are a first-line treatment option for estrogen receptor-positive (ER) breast tumors, in postmenopausal women. Nevertheless, the development of acquired resistance to this therapy is a major drawback.

Differential biological effects of aromatase inhibitors: Apoptosis, autophagy, senescence and modulation of the hormonal status in breast cancer cells.

Estrogen receptor-positive (ER) breast carcinomas are the most common subtype, corresponding to 60% of the cases in premenopausal and 75% in postmenopausal women. The third-generation of aromatase inhibitors (AIs), the non-steroidal Anastrozole (Ana) and Letrozole (Let) and the steroidal Exemestane (Exe), are considered a first-line endocrine therapy for postmenopausal women. Despite their clinical success, the development of resistance is the major setback in clinical practice.

Cannabidiol disrupts apoptosis, autophagy and invasion processes of placental trophoblasts.

Cannabidiol (CBD) is a constituent of Cannabis sativa without psychotropic activity, whose medical benefits have been recognised. However, little is known about the potential toxic effects of CBD on reproductive health. Placental development involves tightly controlled processes of cell proliferation, differentiation, apoptosis, autophagy and migration/invasion of trophoblast cells.

The anti-cancer potential of crotoxin in estrogen receptor-positive breast cancer: Its effects and mechanism of action.

Estrogen receptor-positive (ER) breast cancer is the most diagnosed subtype of breast cancer. Currently, aromatase inhibitors (AIs) are used as first-line treatment option in this type of tumors, however they cause several side effects, which is why new therapeutic approaches are demanding. The South American rattlesnake Crotalus durissus terrificus produces a venom enriched in several bioactive substances, like phospholipases A (PLA).

Unveiling the mechanism of action behind the anti-cancer properties of cannabinoids in ER breast cancer cells: Impact on aromatase and steroid receptors.

Breast cancer is the leading cause of cancer-related death in women worldwide. In the last years, cannabinoids have gained attention in the clinical setting and clinical trials with cannabinoid-based preparations are underway. However, contradictory anti-tumour properties have also been reported.

Discovery of a multi-target compound for estrogen receptor-positive (ER) breast cancer: Involvement of aromatase and ERs.

Despite intense research, breast cancer remains the leading cause of cancer-related death in women worldwide, being estrogen receptor-positive (ER) the most common subtype. Nowadays, aromatase inhibitors (AIs), the selective estrogen receptor modulator (SERM) tamoxifen and the selective estrogen receptor down-regulator (SERD) fulvestrant are used as therapeutic options for ER breast cancer, since they interfere directly with the production of estrogens and with the activation of estrogen-dependent signaling pathways. Despite the success of these treatments, the occurrence of resistance limits their clinical efficacy, demanding the development of novel therapies.

Impact of tetrahydrocannabinol on the endocannabinoid 2-arachidonoylglycerol metabolism: ABHD6 and ABHD12 as novel players in human placenta.

Cannabis use has been increasing worldwide for recreational and medical purposes. Consumption by pregnant women is associated with disturbances in pregnancy outcome, such as low birth weight, prematurity and intrauterine growth retardation, though the underlying biochemical mechanisms are unknown. The endocannabinoid system is involved in several reproductive events and the disruption of its homeostasis by ∆-tetrahydrocannabinol (THC), the main psychoactive cannabinoid, may lead to a negative gestational outcome.

The Cannabinoid Delta-9-tetrahydrocannabinol Disrupts Estrogen Signaling in Human Placenta.

Cannabis consumption is increasing worldwide either for recreational or medical purposes. Its use during gestation is associated with negative pregnancy outcomes such as, intrauterine growth restriction, preterm birth, low birth weight, and increased risk of miscarriage, though the underlying molecular mechanisms are unknown. Cannabis sativa main psychoactive compound, Δ9-tetrahydrocannabinol (THC) is highly lipophilic, and as such, readily crosses the placenta.

The endocannabinoid 2-arachidonoylglycerol promotes endoplasmic reticulum stress in placental cells.

Proliferation, differentiation and apoptosis of trophoblast cells are required for normal placental development. Impairment of those processes may lead to pregnancy-related diseases. Disruption of endoplasmic reticulum (ER) homeostasis has been associated with several reproductive pathologies including recurrent pregnancy loss and preeclampsia.

Cannabis sativa: Much more beyond Δ-tetrahydrocannabinol.

Cannabis is the most used illicit drug worldwide and its medicinal use is under discussion, being regulated in several countries. However, the psychotropic effects of Δ-tetrahydrocannabinol (THC), the main psychoactive compound of Cannabis sativa, are of concern. Thus, the interest in the isolated constituents without psychotropic activity, such as cannabidiol (CBD) and cannabidivarin (CBDV) is growing.

Cannabidiol (CBD) but not tetrahydrocannabinol (THC) dysregulate in vitro decidualization of human endometrial stromal cells by disruption of estrogen signaling.

Decidualization, which comprises proliferation and differentiation of endometrial stromal cells (ESCs), is essential for the establishment of a receptive endometrium and pregnancy to occur. A deregulation of decidualization has been associated with miscarriage, infertility and other pregnancy-related disorders. The role of estradiol (E) on decidualization has already been shown, since it regulates proliferation of ESCs and expression of progesterone receptor.