Prolonged Low-Dose Administration of FDA-Approved Drugs for Non-Cancer Conditions: A Review of Potential Targets in Cancer Cells

Abstract

Though not specifically designed for cancer therapy, several FDA-approved drugs such as metformin, aspirin, and simvastatin have an effect in lowering the incidence of cancer. However, there is a great discrepancy between in vitro concentrations needed to eliminate cancer cells and the plasma concentration normally tolerated within the body. At present, there is no universal explanation for this discrepancy and several mechanisms have been proposed including targeting cancer stem cells (CSCs) or cellular senescence. CSCs are cells with the ability of self-renewal and differentiation known to be resistant to chemotherapy. Senescence is a response to damage and stress, characterized by permanent cell-cycle arrest and apoptotic resistance. Although, for both situations, there are few examples where low concentrations of the FDA-approved drugs were the most effective, there is no satisfactory data to support that either CSCs or cellular senescence are the target of these drugs. In this review, we concisely summarize the most used FDA-approved drugs for non-cancer conditions as well as their potential mechanisms of action in lowering cancer incidence. In addition, we propose that prolonged low-dose administration (PLDA) of specific FDA-approved drugs can be useful for effectively preventing metastasis formation in selected patients.

Keywords: carcinogenesis metastasis; chemoprevention; plasticity; senescence; stem cells.

Figure 1

Potential use of PLDA of FDA-approved drugs to reduce the metastasis formation of specific cancer subtypes in selected populations. In this example, a hypothetical drug X known to reduce the incidence (carcinogenesis) of a specific subtype of triple-negative breast cancer (TNBC, basal-like subtype, with mutation in the CDKN2A gene) may be useful to prevent metastasis in patients carrying this cancer subtype.