A review on mechanisms of resistance to PARP inhibitors

Standard therapy for advanced ovarian cancer (OC) consists of radical debulking cytoreductive surgery followed by adjuvant chemotherapy. An important risk factor for OC is genetic predisposition, with BRCA1 or BRCA2 mutations accounting for the majority of hereditary OC. Mutation in BRCA ultimately causes accumulation of genetic alterations because of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, resulting in tumorigenesis. Poly (ADP?ribose) polymerase (PARP) inhibitors have emerged as a promising approach for managing BRCA?associated cancers, especially high?grade OC and breast cancers. They lead to synthetic lethality in BRCA?mutated cells by stalling the replication forks in homologous recombination?deficient (HR) cells. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) are currently approved by the Food and Drug Administration for OC, breast, and pancreatic cancer indications and are being evaluated for other BRCA?associated cancers. Despite their clinical efficacy, cancer cells generally develop resistance to them through several mechanisms. Understanding these mechanisms is crucial for developing strategies to counter resistance and identify the basic mechanisms of DNA damage response. This review focuses on the mechanism of action of PARP inhibitors, understanding various causes of resistance, and building strategies to overcome PARP inhibitor resistance

Effect of leptin on spatial learning, memory and blood glucose level in streptozotocin induced diabetes mellitus in male wistar albino rats

Background: Diabetes mellitus is known to cause cognitive impairment that can be possibly attributed to deficient levels of leptin in diabetic animals. This study was undertaken to study the effect of administration of leptin on spatial learning, memory and blood glucose levels in diabetic rats.Methods: Rats were divided into three groups. The first group was the control group. Diabetes was induced in groups 2 and 3 by streptozotocin (STZ) injection (60 mg/kg) intraperitoneally. Group 2 received saline while group 3 received leptin (0.1 mg/kg) subcutaneously for 10 days from 4th day of STZ administration. Behavioural assessment was done in T maze after 21 days of the last injection of leptin. Blood glucose levels were also analysed.Results: The number of correct arm entries decreased while time spent being immobile and time spent to reach the correct arm increased in the diabetic group when compared to the control group and correct arm entries increased while time spent immobile and time spent to reach the correct arm decreased with leptin treatment when compared to the diabetic control rats. Blood glucose levels increased in the diabetic rats while leptin administration reduced blood glucose levels in the group 3.Conclusions: Our study suggests that leptin can improve learning and memory while also producing a slight reduction in the blood glucose levels in diabetic rats.