ABSTRACT
Thymoquinone (TQ), isolated from the seeds of Nigella sativa, show moderate efficacy against pancreatic cancer. In the present work we report synthesis and characterization of novel TQ analogs appended with gallate and fluorogallate pharmacophores and evaluation of their effects against pancreatic cancer cell lines for cell viability and induction of apoptosis. The efficacy of the analogs alone or in combination with Gemcitabine was assessed in vitro. LC-MS spectra of ATQTHB and ATQTFB showed major peaks corresponding to expected M+1 fragment at 316.34 and 322.34 respectively. Molecular docking studies revealed good fit for these analogs in the COX-2 protein cavity with better binding energies compared to parent TQ compound. Present TQ analogs exhibit superior anti-proliferative activity, excellent chemo-sensitizing activity against pancreatic cancer in vitro and in combination with Gemcitabine.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzoquinones/chemistry , Benzoquinones/pharmacology , Pancreatic Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Benzoquinones/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Nigella sativa/chemistry , Pancreatic Neoplasms/pathology , Structure-Activity RelationshipABSTRACT
In the process of drug development, there has been an exceptionally high attrition rate in oncological compounds entering late phases of testing. This has seen a concurrent reduction in approved NCEs (new chemical entities) reaching patients. Network pharmacology has become a valuable tool in understanding the fine details of drug-target interactions as well as painting a more practical picture of phenotype relationships to patients and drugs. By utilizing all the tools achieved through molecular medicine and combining it with high throughput data analysis, interactions and mechanisms can be elucidated and treatments reasonably tailored to patients expressing specific phenotypes (or genotypes) of disease, essentially reigning in the phenomenon of drug attrition.
Subject(s)
Drug Design , Neoplasms/drug therapy , Systems Biology , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/metabolism , Drug Approval/statistics & numerical data , Humans , Neoplasms/metabolismABSTRACT
Small molecule inhibitors (SMIs) of murine double minute 2 (MDM2) are known to restore the apoptotic and cell cycle regulatory functions of p53 by disrupting the MDM2-p53 interaction. In principle, these SMIs are not effective against tumours with mutation in the tumour suppressor p53 (mut-p53), which is known to be present in approximately 50% of all cancers. In this study we are reporting, for the first time, that MI-319 in combination with cisplatin induced cell growth inhibition and apoptosis in pancreatic cancer (PC) cells irrespective of their p53 mutational status. MI-319-cisplatin combination synergistically suppressed cell growth (MTT Combination Index [CI]<1) and colony formation (clonogenic assay) and induced apoptosis. Western blot analysis and siRNA silencing studies in mutant as well as p53 null cells highlighted a mechanism involving p73 which is also known to be under the regulation of MDM2, and unlike p53, it is rarely mutated in PC. Down-regulating MDM2 using siRNA enhanced p73 reactivation and increased cell death. Further, the combination effectively reduced tumour growth in both wt-p53 and mut-p53 tumour xenograft models (50% Capan-2 animals were tumour free). Consistent with our in vitro results, remnant tumour tissue analysis showed up-regulation of p73 and the cell cycle regulator p21. In conclusion, this study highlights a new role of MDM2 inhibitors in combination with cisplatin, and thus warrants further clinical investigation in human pancreatic tumours containing both wt-p53 and mut-p53.