Discovering novel derivatives of STAT3 and HDAC inhibitors with anti-tumor activity.

In modern cancer therapy, blockage of more than one target is a standard approach, and there are already many dual-target drugs that can achieve multiple inhibition through a single molecule. Herein, we designed and synthesized a series of novel derivatives with signal transducer and activator of transcription 3 (STAT3) and histone deacetylase (HDAC) inhibitory activity through strategy of combining pharmacophore based on the STAT3 inhibitor E28 and HDAC inhibitor MS-275. Among them, compound 24 (IC50 = 8.22 ± 0.27 µM) showed better anti-tumor activity than the clinical Class I HDAC inhibitor MS-275 (IC50 = 14.65 ± 0.24 µM) in MCF-7 breast cancer cells. Furthermore, the dual inhibition to HDAC and STAT3 of compound 24 was validated by western blot analysis. The study provides new tool compounds for further exploration of STAT3-HDAC pathway inhibitor achieved with a single molecule.

Fluoxetine as a Potential Therapeutic Agent for Inhibiting Melanoma Brain and Lung Metastasis: Induction of Apoptosis, G0/G1 Cell Cycle Arrest, and Disruption of Autophagy Flux.

Brain metastases and lung metastases are major causes of treatment failure and related mortality in melanoma. Fluoxetine hydrochloride (FXT), a widely-used antidepressant, has emerged as a potential anticancer agent in preclinical studies. Previous research has shown its potential to inhibit melanoma. However, its efficacy and the underlying mechanisms in melanoma metastasis, especially concerning brain metastases and lung metastases, remain underexplored. This study investigates FXT's inhibitory effects on melanoma growth and metastasis to the lung and brain. Employing a combination of in vitro assays, we demonstrate FXT's potent suppression of melanoma growth through induction of intrinsic apoptosis, disruption of autophagic flux, and cell cycle arrest at the G0/G1 phase. In in vivo mouse models, we found that FXT exhibits strong inhibitory activity against melanoma brain metastases and lung metastases. Our findings provide a foundation for future clinical exploration of FXT as a novel treatment strategy for melanoma, underscoring its ability to target both primary and metastatic lesions.

The Influence of Exercise on Cancer Risk, the Tumor Microenvironment and the Treatment of Cancer.

There are several modifiable factors that can be targeted to prevent and manage the occurrence and progression of cancer, and maintaining adequate exercise is a crucial one. Regular physical exercise has been shown to be a beneficial strategy in preventing cancer, potentially amplifying the effectiveness of established cancer therapies, alleviating certain cancer-related symptoms, and possibly mitigating side effects resulting from treatment. Nevertheless, the exact mechanisms by which exercise affects tumors, especially its impact on the tumor microenvironment (TME), remain uncertain. This review aims to present an overview of the beneficial effects of exercise in the context of cancer management, followed by a summary of the exercise parameters, especially exercise intensity, that need to be considered when prescribing exercise for cancer patients. Finally, we discuss the influence of exercise on the TME, including its effects on crucial immune cells (e.g., T cells, macrophages, neutrophils, natural killer cells, myeloid-derived suppressor cells, B cells), intratumor angiogenesis, and cancer metabolism. This comprehensive review provides up-to-date scientific evidence on the effects of exercise training on cancer and offers guidance to clinicians for the development of safe and feasible exercise training programs for cancer patients in clinical practice.

Inhibition of TNBC Cell Growth by Paroxetine: Induction of Apoptosis and Blockage of Autophagy Flux.

The strategy of drug repurposing has gained traction in the field of cancer therapy as a means of discovering novel therapeutic uses for established pharmaceuticals. Paroxetine (PX), a selective serotonin reuptake inhibitor typically utilized in the treatment of depression, has demonstrated promise as an agent for combating cancer. Nevertheless, the specific functions and mechanisms by which PX operates in the context of triple-negative breast cancer (TNBC) remain ambiguous. This study aimed to examine the impact of PX on TNBC cells in vitro as both a standalone treatment and in conjunction with other pharmaceutical agents. Cell viability was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, apoptosis was assessed through flow cytometry, and the effects on signaling pathways were analyzed using RNA sequencing and Western blot techniques. Furthermore, a subcutaneous tumor model was utilized to assess the in vivo efficacy of combination therapy on tumor growth. The results of our study suggest that PX may activate the Ca2+-dependent mitochondria-mediated intrinsic apoptosis pathway in TNBC by potentially influencing the PI3K/AKT/mTOR pathway as well as by inducing cytoprotective autophagy. Additionally, the combination of PX and chemotherapeutic agents demonstrated moderate inhibitory effects on 4T1 tumor growth in an in vivo model. These findings indicate that PX may exert its effects on TNBC through modulation of critical molecular pathways, offering important implications for improving chemosensitivity and identifying potential therapeutic combinations for clinical use.