RESUMO
Aberrant activation of hedgehog (Hh) signaling has been implicated in various cancers. Current FDA-approved inhibitors target the seven-transmembrane receptor Smoothened, but resistance to these drugs has been observed. It has been proposed that a more promising strategy to target this pathway is at the GLI1 transcription factor level. GANT61 was the first small molecule identified to directly suppress GLI-mediated activity; however, its development as a potential anti-cancer agent has been hindered by its modest activity and aqueous chemical instability. Our study aimed to identify novel GLI1 inhibitors. JChem searches identified fifty-two compounds similar to GANT61 and its active metabolite, GANT61-D. We combined high-throughput cell-based assays and molecular docking to evaluate these analogs. Five of the fifty-two GANT61 analogs inhibited activity in Hh-responsive C3H10T1/2 and Gli-reporter NIH3T3 cellular assays without cytotoxicity. Two of the GANT61 analogs, BAS 07019774 and Z27610715, reduced Gli1 mRNA expression in C3H10T1/2 cells. Treatment with BAS 07019774 significantly reduced cell viability in Hh-dependent glioblastoma and lung cancer cell lines. Molecular docking indicated that BAS 07019774 is predicted to bind to the ZF4 region of GLI1, potentially interfering with its ability to bind DNA. Our findings show promise in developing more effective and potent GLI inhibitors.
Assuntos
Proteínas Hedgehog , Simulação de Acoplamento Molecular , Piridinas , Pirimidinas , Proteína GLI1 em Dedos de Zinco , Piridinas/farmacologia , Piridinas/química , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Pirimidinas/farmacologia , Pirimidinas/química , Proteínas Hedgehog/metabolismo , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Células NIH 3T3 , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Transdução de Sinais/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacosRESUMO
OBJECTIVES: To investigate whether magnetic resonance imaging (MRI) best detects early malignancy in high-risk women. METHODS: A retrospective, cross-sectional study, carried out at King Abdulaziz University Hospital, Jeddah, Saudi Arabia, included 419 female breast cancer patients aged 16-84 years (mean age of 49). Data were collected from the radiological department's database to compare the MRI, ultrasound (US), and mammography results, with or without tissue biopsy. RESULTS: In diagnosing benign versus malignant lesions, MRI showed significant agreement with tissue biopsy, with high sensitivity (70%) and specificity (87%); its positive predictive value (PPV) was 92% and negative predictive value (NPV) was 56%. While US has a PPV of 84% and NPV of 63%; with a sensitivity (79%) and specificity (71%). In patients without tissue biopsy, there was little difference between mammography and US compared with MRI results. CONCLUSION: Magnetic resonance imaging is more effective than US and mammography for early detection of BC. It showed high sensitivity in detecting breast lesions and high specificity in characterizing their nature when correlated with pathological results. Ultrasound screening followed by MRI is suggested for undetected or suspected lesions. This will increase the breast lesion detection rate, reduce unneeded tissue biopsies, and enhance the disease's survival rate.