jib-04 and Lung-Neoplasms

JIB‑04 is a structurally unique small molecule, known to exhibit anticancer activity and to inhibit the growth of human lung cancer and prostate cancer cell lines. However, the anticancer effect of JIB‑04 against human hepatic carcinoma, and its underlying mechanisms, are still unclear. In the present study, MHCC97H and HepG2 cells were employed to investigate the anticancer effects of JIB‑04 on cell viability and apoptosis. Annexin V/PI staining, a CCK‑8 assay and western blot analysis demonstrated that JIB‑04 induced apoptosis in MHCC97H and HepG2 cells, which was evidenced by the expression of proapoptotic and apoptotic proteins including p53, Bak, Bax, caspase‑3 and caspase‑9. Subsequently, the expression trends of Bcl‑2 and p53 were reversed after co‑treatment with pifithrin‑α (PFT‑α, a p53 inhibitor). The results revealed that JIB‑04 suppressed the cell viability of MHCC97H and HepG2 cells in a concentration‑dependent manner. Meanwhile, it was also demonstrated that JIB‑04 effectively triggered MHCC97H and HepG2 cell apoptosis by downregulating Bcl‑2/Bax expression, and upregulating proapoptotic and apoptotic protein expression via the p53/Bcl2/caspase signaling pathway. JIB‑04 had effects on the inhibition of cell viability and the induction of apoptosis in MHCC97H and HepG2 cells. The underlying mechanism of action of JIB‑04 was associated with the p53/Bcl‑2/caspase signaling pathway. Our findings provide a foundation for understanding the anticancer effect of JIB‑04 on MHCC97H and HepG2 cells, and suggested that JIB‑04 may be a promising therapeutic agent in human liver cancer.

Topics: Aminopyridines; Caspases; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Hydrazones; Lung Neoplasms; Male; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tumor Suppressor Protein p53

Although non-small cell lung cancer (NSCLC) patients benefit from standard taxane-platin chemotherapy, many relapse, developing drug resistance. We established preclinical taxane-platin-chemoresistance models and identified a 35-gene resistance signature, which was associated with poor recurrence-free survival in neoadjuvant-treated NSCLC patients and included upregulation of the JumonjiC lysine demethylase KDM3B. In fact, multi-drug-resistant cells progressively increased the expression of many JumonjiC demethylases, had altered histone methylation, and, importantly, showed hypersensitivity to JumonjiC inhibitors in vitro and in vivo. Increasing taxane-platin resistance in progressive cell line series was accompanied by progressive sensitization to JIB-04 and GSK-J4. These JumonjiC inhibitors partly reversed deregulated transcriptional programs, prevented the emergence of drug-tolerant colonies from chemo-naive cells, and synergized with standard chemotherapy in vitro and in vivo. Our findings reveal JumonjiC inhibitors as promising therapies for targeting taxane-platin-chemoresistant NSCLCs.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Benzazepines; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Disease-Free Survival; Drug Resistance, Neoplasm; Enzyme Inhibitors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Histones; Humans; Hydrazones; Jumonji Domain-Containing Histone Demethylases; Lung Neoplasms; Methylation; Mice; Neoadjuvant Therapy; Pyrimidines; Taxoids; Transcription, Genetic