Abstract
Advances in treatment strategies together with an earlier diagnosis have considerably increased the average survival of cancer patients over the last four decades. Nevertheless, despite the growing number of new antineoplastic agents introduced each year, there is still no adequate therapy for problematic malignancies such as pancreatic, lung and stomach cancers. Consequently, it is important to ensure that existing drugs used to treat other types of cancers, and potentially other diseases, are not overlooked when searching for new chemotherapy regimens for these problematic cancer types. We describe a screening approach that identifies chemotherapeutics for the treatment of lung and pancreatic cancers, based on drugs already approved for other applications. Initially, the 1280 chemically and pharmacologically diverse compounds from the Prestwick Chemical Library® (PCL) were screened against A549 (lung cancer) and PANC-1 (pancreatic carcinoma) cells using the PrestoBlue fluorescent-based cell viability assay. More than 100 compounds from the PCL were identified as hits in one or both cell lines (80 of them, being drugs used to treat diseases other than cancer). Selected PCL hits were further evaluated in a dose-response manner. Promising candidates for repositioning emanating from this study include antiparasitics, cardiac glycosides, as well as the anticancer drugs vorinostat and topotecan.
Highlights
Cancer is amongst the worlds leading causes of death, with the greatest economic impact from premature death and disability from all causes of death worldwide [1,2]
Experiments were conducted in 384-well format in reverse mode (PCL compounds were dispensed on the plates before seeding of the cells) due to the high amount of compounds to be screened in multiple conditions and the semi-automation required
The Prestwick Chemical Library® (PCL) containing 1280 drugs and drug-like molecules was screened against A549 and PANC-1 cells providing a list of compounds that could be active against highly problematic lung and pancreatic cancers
Summary
Cancer is amongst the worlds leading causes of death, with the greatest economic impact from premature death and disability from all causes of death worldwide [1,2]. Over the last few decades improvements in treatment strategies, together with an earlier diagnosis, have significantly increased the average survival of cancer patients [5,6]. There is a wide variation in response rates between cancer types, with, for example, the predicted ten-year net survival for patients diagnosed during 2010–2011 in the UK. Despite the increasing number of new anticancer drugs introduced each year [8], no adequate therapy exists for problematic malignancies such as pancreatic, lung, brain and stomach cancers. It is important to ensure that existing drugs used to treat other types of cancers, and potentially other diseases, are not overlooked when searching for new chemotherapy regimens for these problematic cancer types
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