BRD4 Inhibition as a Strategy to Prolong the Response to Standard of Care in Estrogen Receptor-Positive Breast Cancer.

Breast cancer is the most commonly occurring malignancy in women and the second most common cause of cancer-related deaths. ER+ breast cancer constitutes approximately 70% of all breast cancer cases. The standard of care for ER+ breast cancer involves estrogen antagonists such as tamoxifen or fulvestrant in combination with CDK4/6 inhibitors such as palbociclib. However, these treatments are often not curative, with disease recurrence and metastasis being responsible for patient mortality. Overexpression of the epigenetic regulator, BRD4, has been shown to be a negative prognostic indicator in breast cancer, and BET family inhibitors such as ARV-825 and ABBV-744 have garnered interest for their potential to improve and prolong the response to current therapeutic strategies. The current work examined the potential of utilizing ARV-825 and ABBV-744 to increase the effectiveness of tamoxifen or fulvestrant plus palbociclib. ARV-825 was effective in both p53 wild-type (WT) breast tumor cells and in cells lacking functional p53 either alone or in combination with tamoxifen, while the effectiveness of ABBV-744 was limited to fulvestrant plus palbociclib in p53 WT cells. These differential effects may be related to the capacity to suppress c-Myc, a downstream target of BRD4.

Thymoquinone: Review of Its Potential in the Treatment of Neurological Diseases.

Thymoquinone (TQ) possesses anticonvulsant, antianxiety, antidepressant, and antipsychotic properties. It could be utilized to treat drug misuse or dependence, and those with memory and cognitive impairment. TQ protects brain cells from oxidative stress, which is especially pronounced in memory-related regions. TQ exhibits antineurotoxin characteristics, implying its role in preventing neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. TQ's antioxidant and anti-inflammatory properties protect brain cells from damage and inflammation. Glutamate can trigger cell death by causing mitochondrial malfunction and the formation of reactive oxygen species (ROS). Reduction in ROS production can explain TQ effects in neuroinflammation. TQ can help prevent glutamate-induced apoptosis by suppressing mitochondrial malfunction. Several studies have demonstrated TQ's role in inhibiting Toll-like receptors (TLRs) and some inflammatory mediators, leading to reduced inflammation and neurotoxicity. Several studies did not show any signs of dopaminergic neuron loss after TQ treatment in various animals. TQ has been shown in clinical studies to block acetylcholinesterase (AChE) activity, which increases acetylcholine (ACh). As a result, fresh memories are programmed to preserve the effects. Treatment with TQ has been linked to better outcomes and decreased side effects than other drugs.

Molecular Mechanisms of Thymoquinone as Anticancer Agent.

Thymoquinone (TQ), the bioactive constituent of Nigella Sativa seeds, is a well-known natural compound for the management of several types of cancers. The anti-cancer properties of thymoquinone are thought to be operated via intervening with various oncogenic pathways, prevention of inflammation and oxidative stress, inhibition of angiogenesis and metastasis, and induction of apoptosis, as well as up-regulation and down-regulation of specific tumor suppressor genes and tumor promoting genes, respectively. The proliferation of various tumor cells is inhibited by TQ via induction of cell cycle arrest, disruption of the microtubule organization, and downregulating cell survival protein expression. TQ induces G1 phase cell cycle arrest in human breast cancer, colon cancer and osteosarcoma cells through inhibiting the activation of cyclin E or cyclin D and up-regulating p27 and p21, a cyclin dependent kinase (Cdk) inhibitor. TQ concentration is a significant factor in targeting a particular cell cycle phase. While high concentration of TQ induces G2 phase arrest in human breast cancer (MCF-7) cells, low concentration causes S phase arrest. This review article provides mechanistic insights into the anticancer properties of thymoquinone.