Background: Epigenetic modification influences androgen receptor (AR) activation, often resulting in prostate cancer (PCa) development and progression. Silencing histone-modifying enzymes (histone deacetylases-HDACs) either genetically or pharmacologically suppresses PCa proliferation in preclinical models of PCa; however, results from clinical studies were not encouraging. Similarly, PCa patients eventually become resistant to androgen ablation therapy (ADT). Our goal is to develop dual-acting small molecules comprising antiandrogen and HDAC-inhibiting moieties that may overcome the resistance of ADT and effectively suppress the growth of castration-resistant prostate cancer (CRPC). Methods: Several rationally designed antiandrogen-equipped HDAC inhibitors (HDACi) were synthesized, and their efficacy on CRPC growth was examined both in vitro and in vivo. Results: While screening our newly developed small molecules, we observed that SBI-46 significantly inhibited the proliferation of AR⁺ CRPC cells but not AR^- CRPC and normal immortalized prostate epithelial cells (RWPE1) or normal kidney cells (HEK-293 and VERO). Molecular analysis confirmed that SBI-46 downregulated the expressions of both AR⁺ and AR-splice variants (AR-SVs) in CRPC cells. Further studies revealed the downregulation of AR downstream (PSA) events in CRPC cells. The oral administration of SBI-46 abrogated the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV in xenotransplanted nude mice models. Further, immunohistochemical analysis confirmed that SBI-46 inhibits AR signaling in xenografted tumor tissues. Conclusion: These results demonstrate that SBI-46 is a potent agent that inhibits preclinical models of CRPC by downregulating the expressions of both AR and AR-SV. Furthermore, these results suggest that SBI-46 may be a potent compound for treating CRPC.

Cancer remains one of the most formidable public health challenges, with breast, lung, and colon cancer being the most prevalent and deadly cancer types worldwide[1, 2]. It has become increasingly clear, that aside from genetic disposition, lifestyle choices and environmental factors have a profound impact on increasing an individual’s risk of developing cancer[3-6]. Exposure to harmful environmental agents—ranging from air pollutants to toxic chemicals—significantly influences cancer incidence, particularly in vulnerable populations [7]. To effectively combat these cancers and reduce disparities among patients/survivors, public health strategies must be refined to address environmental risks, improve early detection, and ensure equitable access to care. This Research Topic focuses on advancing our understanding of the specific environmental exposures implicated in breast, lung, and colon cancer, primarily focusing on informing and advancing public health strategies. By exploring breakthrough information related to these cancers, we seek to uncover novel insights into the associations between these environmental exposures and their impact on carcinogenesis.The relationship between environmental risk factors and cancer incidence is well-documented, yet it often lacks visibility in public discourse. Carcinogenic substances like tobacco, industrial pollutants, etc. are known to increase cancer incidence, particularly for lung, breast, and colon cancers. For example, prolonged exposure to air pollutants, such as particulate matter, has been directly linked to an increased incidence of lung cancer [8]. Similarly, chemicals found in pesticides and plastics have been associated with breast cancer, while environmental influences on diet, such as the availability of processed foods, contribute to the incidence of colon cancer [9-11]. In this Research Topic, several studies from various parts of the world as well as the United States present evidence of a growing risk of breast, colon, and lung cancer incidence due to prolonged exposure to environmental pollutants. Godinho dos Santos et al., [12] in their study, showed that occupational exposure to pesticides in rural working women induced significant changes in the levels of cytokines necessary for tumor control and were positively correlated with worse prognostic outcomes. A meta-analysis study by Liu et al. [13] demonstrated significant associations between exposure to endocrine-disrupting chemicals (EDCs), which have the potential to interfere with the function of normal hormones, and an increased risk of breast cancer. They found that breast cancer risk was increased by exposure to certain EDC congeners and their metabolites, such as benzene, chlordane, hexachlorocyclohexane, and polychlorinated biphenyls. Similarly, Ying et al. [14] conducted a prospective cohort study to determine the relationship between Bisphenol A (BPA) exposure and cancer mortality. BPA, an environmental phenol, is utilized in various products, including baby bottles, and food containers [15], and has been shown to be detectable in more than 90% of urine samples in the general population in the United States [16], promoting some states to enforce regulations to restrict the use of BPA. The authors of this study determined that a lower level of BPA of less than 1.99 ng/mL was associated with a higher risk of cancer mortality. In their scoping review on military environmental exposures (MEE) including volatile organic compounds (VOCs), endocrine-disrupting chemicals (EDCs), tactile herbicides, airborne hazards and open burn pits (AHOBP), and depleted uranium on the risk of breast cancer among service members and Veterans, Jester et al. [17] determined that MEE poses a unique risk to women veterans who were affected by MEE during their service. However, the authors concede that further studies are needed to validate these findings owing to the mixed and limited availability of literature on MEE and breast cancer among veterans. Socio-economic demographics, resulting in higher carcinogen exposures and higher behavioral risk factors such as diet, physical activity, and obesity, or substance use such as smoking and alcohol consumption, also play integral roles in increasing cancer risk [18-21]. For example, one-third of cancer deaths in the United States are attributed to diet, lack of physical activity, and obesity, while another third is correlated to exposure to tobacco products [22]. In their perspective article, Atchade et al. [23] highlight changes in Westernized dietary patterns in the United States as a significant contributor impacting the colonic microbiome and contributing to the recent surge of early-onset CRC (EOCRC). To determine the correlation between caffeine consumption and the prevalence of colon cancer, Qu et al. [24] applied weighted logistic regression to the National Health and Nutrition Examination Survey (NHANES) dataset to evaluate correlations. They determined a potential dose–response relationship between an increased risk of colon cancer and higher caffeine intake levels. In continuation of their previous work demonstrating alcohol exposure selectively activates mammalian p38 mitogen-activated protein kinase (MAPK) in breast cancer cells, in their current study, Li et al. [25] aimed to determine if Pirfenidone (PFD), an antifibrotic compound and pharmacological inhibitor of p38γ MAPK, could inhibit alcohol-induced promotion of breast cancer. Their results demonstrate that PFD successfully inhibited mammary tumor growth and alcohol-promoted metastasis, suggesting that this agent, which is currently approved for the treatment of idiopathic pulmonary fibrosis, could be re-purposed and used to treat aggressive breast cancer and alcohol-promoted mammary tumor progression. It is also important to note that exposure to environmental carcinogens is not evenly distributed across populations, creating environmental...