RESUMEN
Bisphenol A (BPA), chemically known as 2,2-bis(4-hydroxyphenyl) propane, is one of the most common endocrine-disrupting chemicals in our environment. Long-term or high-dose exposure to BPA may lead to testicular damage and adversely affect male reproductive function. In vivo studies on rodents have demonstrated that BPA triggers apoptosis in testicular cells through both intrinsic and extrinsic pathways. Further in vitro studies on spermatogonia, Sertoli cells, and Leydig cells have all confirmed the pro-apoptotic effects of BPA. Given these findings, apoptosis is considered a primary mode of cell death induced by BPA in testicular tissue. In addition, BPA promotes autophagy by altering the activity of the Akt/mTOR pathway and upregulating the expression of autophagy-related genes and proteins. Recent studies have also identified ferroptosis as a significant contributing factor to BPA-induced testicular damage, further complicating the landscape of BPA's effects. This review summarizes natural substances that mitigate BPA-induced testicular damage by inhibiting these cell death pathways. These findings not only highlight potential therapeutic strategies but also underscore the need for further research into the underlying mechanisms of BPA-induced toxicity, particularly as it pertains to human health risk assessment and the development of more effective BPA management strategies.
RESUMEN
BACKGROUND AND PURPOSE: The mammalian target of rapamycin (mTOR) pathway plays critical roles in intrinsic chemoresistance by regulating Fanconi anaemia complementation group D2 (FANCD2) expression. However, the mechanisms by which mTOR regulates FANCD2 expression and related inhibitors are not clearly elucidated. Extracts of Centipeda minima (C. minima) showed promising chemosensitizing effects by inhibiting FANCD2 activity. Here, we have aimed to identify the bioactive chemosensitizer in C. minima extracts and elucidate its underlying mechanism. EXPERIMENTAL APPROACH: The chemosensitizing effects of arnicolide C (ArC), a bioactive compound in C. minima, on non-small cell lung cancer (NSCLC) were investigated using immunoblotting, immunofluorescence, flow cytometry, the comet assay, small interfering RNA (siRNA) transfection and animal models. The online SynergyFinder software was used to determine the synergistic effects of ArC and chemotherapeutic drugs on NSCLC cells. KEY RESULTS: ArC had synergistic cytotoxic effects with DNA cross-linking drugs such as cisplatin and mitomycin C in NSCLC cells. ArC treatment markedly decreased FANCD2 expression in NSCLC cells, thus attenuating cisplatin-induced FANCD2 nuclear foci formation, leading to DNA damage and apoptosis. ArC inhibited the mTOR pathway and attenuated mTOR-mediated expression of E2F1, a critical transcription factor of FANCD2. Co-administration of ArC and cisplatin exerted synergistic anticancer effects in the A549 xenograft mouse model by suppressing mTOR/FANCD2 signalling in tumour tissues. CONCLUSION AND IMPLICATIONS: ArC suppressed DNA cross-linking drug-induced DNA damage response by inhibiting the mTOR/E2F1/FANCD2 signalling axis, serving as a chemosensitizing agent. This provides insight into the anticancer mechanisms of ArC and offers a potential combinatorial anticancer therapeutic strategy.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Anemia de Fanconi , Neoplasias Pulmonares , Humanos , Animales , Ratones , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/farmacología , Neoplasias Pulmonares/patología , Serina-Treonina Quinasas TOR/metabolismo , ADN , Mamíferos/metabolismo , Factor de Transcripción E2F1/metabolismo , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/metabolismoRESUMEN
SCOPE: This study aims to investigate the anticancer properties of Citrus grandis 'Tomentosa' (CGT) in non-small cell lung cancer (NSCLC). METHODS AND RESULTS: The ethanol extract of CGT (CGTE) is prepared by using anhydrous ethanol and analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), revealing that the main chemical components in CGTE are flavonoids and coumarins, such as naringin, rhoifolin, apigenin, bergaptol, and osthole. CGTE at concentrations without inducing cell death significantly inhibits cell proliferation via inducing cell cycle G1 phase arrest by MTT, colony formation, and flow cytometry assays, implying that CGT has anticancer potential. CGTE markedly inhibits the activity of Skp2-SCF E3 ubiquitin ligase, decreases the protein level of Skp2, and promotes the accumulation of p27 by co-immunoprecipitation (co-IP) and in vivo ubiquitination assay; whereas Skp2 overexpression rescues the effects of CGTE in NSCLC cells. In subcutaneous LLC allograft and A549 xenograft mouse models, CGTE, without causing obvious side effects in mice, significantly inhibits lung tumor growth by targeting the Skp2/p27 signaling pathway. CONCLUSION: These findings demonstrate that CGTE efficiently inhibits NSCLC proliferation both in vitro and in vivo by targeting the Skp2/p27 signaling pathway, suggesting that CGTE may serve as a therapeutic candidate for NSCLC treatment.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Citrus , Neoplasias Pulmonares , Humanos , Animales , Ratones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Citrus/química , Cromatografía Liquida , Espectrometría de Masas en Tándem , Proteínas Ligasas SKP Cullina F-box , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismoRESUMEN
Skp1-Cul1-F-box protein (SCF) ubiquitin E3 ligases play important roles in cancer development and serve as a promising therapeutic target in cancer therapy. Brusatol (Bru), a known Nrf2 inhibitor, holds promise for treating a wide range of tumors; however, the direct targets of Bru and its anticancer mode of action remain unclear. In our study, 793 Bru-binding candidate proteins were identified by using a biotin-brusatol conjugate (Bio-Bru) followed by streptavidin-affinity pull down-based mass spectrometry. We found that Bru can directly bind to Skp1 and disrupt the interactions of Skp1 with the F-box protein Skp2, leading to the inhibition of the Skp2-SCF E3 ligase. Bru inhibited both proliferation and migration via promoting the accumulation of the substrates p27 and E-cadherin; Skp1 overexpression attenuated while Skp1 knockdown enhanced these effects of Bru in non-small cell lung cancer (NSCLC) cells. Moreover, Bru binding to Skp1 also inhibited the ß-TRCP-SCF E3 ligase. In both subcutaneous and orthotopic NSCLC xenografts, Bru significantly inhibited the growth and metastasis of NSCLC through targeting SCF complex and upregulating p27 and E-cadherin protein levels. These data demonstrate that Bru is a Skp1-targeting agent that may have therapeutic potentials in lung cancer.