Targeting cancer stem cells expressing an embryonic signature with anti-proteases to decrease their tumor potential

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.

HIV‐protease inhibitors for the treatment of cancer: Repositioning HIV protease inhibitors while developing more potent NO‐hybridized derivatives?

“…The ability of HIV‐PIs to specifically target CSCs derived from tumors with distinct origins opens the prospect of using HIV‐PIs to treat patients with aggressive malignances. Lopinavir was found to be particularly efficacious, as it abolished self‐renewal and provoked apoptosis of CSCs, thus inhibiting formation of CSC‐induced allografts in vivo …”

“…Lopinavir was found to be particularly efficacious, as it abolished self-renewal and provoked apoptosis of CSCs, thus inhibiting formation of CSC-induced allografts in vivo. 17 Apart from a direct tumoricidal effect, HIV-PIs suppress growth of adenocarcinomas of lung, breast, colon and hepatic origin by blocking angiogenesis and MMP activity. 18 Indinavir and saquinavir also inhibit the appearance and regression of angioproliferative KS-like lesions in nude mice.…”

Cancer stem cells: a challenging paradigm for designing targeted drug therapies

“…), and ESC-associated pathways are activated in CSCs [51]. Table 1 lists key transcription factors [2,6,8,25,[52][53][54][55][56][57][58][59][60][61][62][63][64][65][66], surface markers [6][7][8]11,18,19,25,52,53,59,60,[67][68][69][70][71][72], and signaling pathways [1,4,6,8,11,17,18,52,58,60,71,73] that are common in ESCs and CSCs. However, CSCs in glioblastoma multiforme (GBM) and melanomas express Nestin, whereas Bmi-1 is expressed in CSCs of breast and prostate cancers, and n...…”

Tailoring Peptidomimetics for Targeting Protein–Protein Interactions

“…Delineation of signaling pathways involved in the development of cancerous phenotypes, including decreased cell apoptosis, rapid cell proliferation, and increased cell survival, have enabled development of therapeutic agents targeting critical drivers (27)(28)(29)(30)(31)(32). Traditional (and relatively nonspecific) "catch-all" therapies have focused on DNA chelating agents (e.g., cisplatin) and radiotherapy aimed at targeting rapidly dividing cells (33)(34)(35).…”