Abstract
Major advances in our understanding of the molecular mechanisms underlying the malignant progression of human cancers have been borne over the last decade. Such insight led to the development of several novel targeted anticancer therapies intended to improve patient outcomes. Yet even when such targeted approaches are applied in conjunction with conventional chemotherapies only modest improvements in overall survivability are reported for many tumor types. Accordingly, tumor recurrence and metastasis have remained major clinical barriers that demand novel solutions. Tumor heterogeneity and acquired drug resistance are cited as the primary culprits underlying the poor efficacy of targeted and conventional chemotherapeutics. Even more persuasive are arguments suggesting that a rare population of cancer stem cells (CSC) form the basis of therapeutic resistance and tumor recurrence. CSCs maintain the capacity for self-renewal, and are capable of re-establishing heterogeneous tumor populations following therapeutic interventions. More importantly, CSCs adeptly evade most currently applied therapies through their heightened apoptosis resistance and slow cell cycling. We have previously established that 5-(N, N-hexamethylene) amiloride (HMA) effectively depletes breast cancer cells irrespective of molecular subtype, proliferative status or species of origin. Further to this, we found HMA discriminates normal, non-transformed cells from cancer cells, suggesting its potential utility as an anticancer therapeutic. We hypothesized that HMA would effectively eliminate tumor cells across all tumor types, and their respective isolated CSC populations. Here we demonstrate through in vitro studies that HMA is cytotoxic against CSCs and bulk populations of cancer cells derived from various tissues (pancreas, bladder, liver, lung, colon, brain). These studies not only complement our ongoing mechanistic studies in animal-based and breast cancer cell models but also firmly establish the mode of cell death elicited by HMA as a rational approach for targeting cancer types which may have limited treatment options.