Targeting transcriptional kinase of CDK7 halts proliferation of multiple myeloma cells by modulating the function of canonical NF-kB pathway and cell cycle regulatory proteins.

Multiple myeloma (MM) is an incurable plasma cell neoplasm. Despite several effective frontline therapeutic regimens, including Bortezomib (BTZ), relapse is almost inevitable; therefore, better therapeutic modalities to improve the outcomes are needed. Cyclin-dependent kinases (CDKs) are an essential constituent of the cellular transcriptional machinery and tumors including MM are critically dependent on transcription to maintain their oncogenic state. In the present study, we explored the efficacy of THZ1, a covalent CDK7 inhibitor in MM treatment using Bortezomib resistant (H929BTZR) cells and zebrafish xenografts. THZ1 showed anti-myeloma activity in the models of MM but had no effect on healthy CD34+ cells. THZ1 suppresses phosphorylation of carboxy-terminal domain of RNA polymerase II and downregulates the transcription of BCL2 family of proteins both in H929BTZS and H929BTZR cells leading to G1/S arrest and apoptosis. THZ1 mediates inhibition of bone marrow stromal cells-induced proliferation and activation of NF-kB signaling. The data derived from zebrafish xenografts of MM demonstrate that THZ1 combined with BTZ synergistically reduces tumor growth in zebrafish embryos. Collectively, our results reveal that THZ1 alone as well as in combination with BTZ has effective anti-myeloma activity.

Therapeutic potential of root and stem bark of wild medicinal plant Ziziphus mauritiana (Lamk.) against silica induced toxicity in Wistar albino rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Ziziphus mauritiana (Lamk.) of the family Rhamnaceae is a traditional herbal medicinal plant commonly called as 'ber' (Indian jujube). It is traditionally used as food source and helps in treatment of various diseases like malaria, asthma, diarrhoea, typhoid, diabetes, skin diseases and acts as a pain killer. AIM OF THE STUDY: This study aimed to evaluate the ability of extracts of barks of root and stem of Ziziphus mauritiana (ZM) to cure silica induced toxicity in Wistar albino rats. MATERIALS AND METHODS: Experiments carried out on the acute toxicity studies of silica and therapeutic potential of ZM extracts were based on OECD guidelines and from these results lethal dose (LD50) values were determined. Silica was administered by IP injection at 20 mg/kg b.w. for 10 days and roots and stem barks extracts of ZM were fed orally by gavage at 400 mg/kg b.w. for 21 days. Assessments of biochemical, haematological parameters as well as liver histological examination were performed in the study. RESULTS: After 21 days of oral feeding of extracts of root and stem of ZM, it was found to alter the liver histology. Significant decrease in enzymes such as ALT, AST, ALP, LDH and urea, creatinine and uric acid levels in serum were recorded. Treatment with extracts could help enzymatic activity of liver antioxidant enzymes to settle towards normal level and significant decrease in the lipid peroxidation along with increase in the value of GSH in liver, was also observed. In addition, extracts of ZM also helped to reduce the serum NO, IL-6 and TNF-α level. CONCLUSION: Results of this study has suggested that the extracts of root and stem bark of ZM can be used for therapeutic purpose to prevent silica induced toxicity. ZM extracts could be utilised as natural antioxidant and immunotherapeutic medicines to protect silica induced cell damage.