Abstract
Cancer stem cells (CSCs) are a specific subset of cancer cells that sustain tumor growth and dissemination. They might represent a significant treatment target to reduce malignant progression and prevent tumor recurrence. In solid tumors, several hierarchically organized CSC clones coexist, even within a single tumor. Among them, CSCs displaying an embryonic stem cell ‘stemness' signature, based on the expression of Oct-4, Nanog and Sox2, are present in distinct high-grade tumor types associated with poor prognosis. We previously designed a model to isolate pure populations of these CSCs from distinct solid tumors and used it to screen for molecules showing selective toxicity for this type of CSC. Here we show that human immunodeficiency virus (HIV)-protease inhibitors (HIV-PIs) specifically target CSCs expressing an embryonic signature derived from tumors with distinct origins. They reduced proliferation in a dose-dependent manner with a higher specificity as compared with the total population of cancer cells and/or healthy stem cells, and they were efficient in inducing cell death. Lopinavir was the most effective HIV-PI among those tested. It reduced self-renewal and induced apoptosis of CSCs, subsequently impairing in vivo CSC-induced allograft formation. Two key pharmacophores in the LPV structure were also identified. They are responsible for the specificity of CSC targeting and also for the overall antitumoral activity. These results contribute to the identification of molecules presenting selective toxicity for CSCs expressing an embryonic stemness signature. This paves the way to promising therapeutic opportunities for patients suffering from solid cancer tumors of poor prognosis.
Highlights
Vast cancer stem cell (CSC) phenotypic diversity has been described in distinct solid tumors based on the expression of cell surface markers such as CD133, CD44,6–9 the activity of enzymes such as ALDH or the ability to exclude cytotoxic molecules.[10,11] Co-expression of any of these markers makes it difficult to isolate a sufficient amount of pure Cancer stem cells (CSCs) populations for drug screening
We show that among Human immunodeficiency virus (HIV)-protease inhibitors (PIs), lopinavir (LPV), one of the most widely used HIV-PIs, efficiently distinguishes CSCs among cancer cells and selectively reduces proliferation and self-renewal of Oct-4-expressing CSCs isolated from different types of solid tumor.[14]
Among the PIs tested, we found that nelfinavir (NFV), saquinavir (SQV) and RTV were more efficient in reducing CSC growth
Summary
Vast CSC phenotypic diversity has been described in distinct solid tumors based on the expression of cell surface markers such as CD133, CD44,6–9 the activity of enzymes such as ALDH or the ability to exclude cytotoxic molecules.[10,11] Co-expression of any of these markers makes it difficult to isolate a sufficient amount of pure CSC populations for drug screening. CSC purification requires a reliable signature, which is somewhat inconsistent with the fickle behavior of these cells.[3,4] From a functional standpoint, CSCs are defined by their ability to self-renew, which is essential for their maintenance. This property is important to indefinitely perpetuate the growth of a malignant cell population[12] and to recapitulate the hierarchy of the original tumor.[5,13] Recently, we used a self-renewal gene tracking strategy to isolate pure populations of CSCs upon. Eradication using specific monoclonal antibodies to surface markers was inappropriate as no common cell surface markers have been identified in Oct-4expressing CSCs.[14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
