Abstract
Simple SummaryA limitation to successful therapeutic outcomes for breast and other cancer patients is the ability of small subsets of tumor cells to resist the apoptotic cell death provoked by currently employed therapeutic agents. These therapy-resistant cancer stem cell populations can then seed recurrent tumors and metastatic lesions, compromising the efficacy of the treatment regimen. The aim of our study was to assess the hypothesis that cationic amphiphilic drugs (CADs), which induce tumor cell death via the unrelated programmed necrotic mechanism, exhibit efficacy toward cancer stem cell populations that are resistant to currently employed therapeutics. We found that the therapy-resistant stem-like subpopulation of cells from a variety of breast cancer models are as sensitive to CADs as the bulk population. Our observations imply that the incorporation of cationic amphiphilic anticancer agents into existing therapeutic regimens could ultimately improve breast cancer patient outcomes by minimizing tumor recurrence and metastatic outgrowth.The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species but acts poorly toward non-transformed cells derived from multiple tissues. Here, we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate, and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Our observations expose a key vulnerability intrinsic to cancer stem cells and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment.
Highlights
Studies in both hematological and solid tumor malignancies support the notion that tumor-initiating or cancer stem cells (CSCs)—a rare, relatively quiescent, and highly tumorigenic cancer cell population endowed with the capacity for self-renewal, anchorage independence, and multilineage differentiation—harbor intrinsic therapy resistance mechanisms and pose significant clinical challenges [1–5]
To assess the ability of hexamethylene amiloride (HMA) to eradicate breast CSCs (BCSCs), we first examined the impact of HMA pretreatment on secondary sphere formation [43–45] by cultured human breast cancer cell lines
To discern whether therapy-resistant BCSC subpopulations are sensitive to HMA, we examined the sphere-forming capabilities of sorted cells after treatment with HMA or the apoptosis-inducing conventional chemotherapeutic agent cisplatin (CIS), or docetaxel (DTX) together with doxorubicin (DOX), at levels similar to their EC50 s for cytotoxicity toward the total cell population (Figure 1D)
Summary
Studies in both hematological and solid tumor malignancies support the notion that tumor-initiating or cancer stem cells (CSCs)—a rare, relatively quiescent, and highly tumorigenic cancer cell population endowed with the capacity for self-renewal, anchorage independence, and multilineage differentiation—harbor intrinsic therapy resistance mechanisms and pose significant clinical challenges [1–5]. While a potentially promising strategy, therapeutically targeting CSCs presents unique obstacles considering their notorious resistance to apoptotic death and capacity to launch primary tumor recurrence and metastases, even in cases of apparent complete clinical remission [3,10]. Novel therapeutics that engage non-apoptotic cell death pathways to kill CSCs and other apoptosis-resistant tumor cells warrant investigation. HMA reduces the viability of breast cancer cells of differing molecular profiles with equal efficiency [17], which is significant as breast cancer subtypes (luminal or basal, estrogen/progesterone receptor-positive (ER/PR+), HER2−amplified (HER2+), or receptor-negative (ER/PR/HER2−)) are variably resistant to chemotherapeutics and targeted drugs [18]. HMA is effective in eradicating both dividing and non-dividing cells [17], distinguishing it from cytotoxic agents that are employed clinically to kill actively proliferating cells but that can leave behind the quiescent
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