Abstract
ObjectivesSalinomycin is a polyether antibiotic with selective activity against human cancer stem cells. The impact of salinomycin on patient-derived primary human colorectal cancer cells has not been investigated so far. Thus, here we aimed to investigate the activity of salinomycin against tumor initiating cells isolated from patients with colorectal cancer.MethodsPrimary tumor-initiating cells (TIC) isolated from human patients with colorectal liver metastases or from human primary colon carcinoma were exposed to salinomycin and compared to treatment with 5-FU and oxaliplatin. TICs were injected subcutaneously into NOD/SCID mice to induce a patient-derived mouse xenograft model of colorectal cancer. Animals were treated either with salinomycin, FOLFOX regimen, or salinomycin and FOLFOX. Human colorectal cancer cells were used to delineate an underlying molecular mechanism of salinomycin in this tumor entity.ResultsApplying TICs isolated from human patients with colorectal liver metastases or from human primary colon carcinoma, we demonstrated that salinomycin exerts increased antiproliferative activity compared to 5-fluorouracil and oxaliplatin treatment. Consistently, salinomycin alone or in combination with FOLFOX exerts superior antitumor activity compared to FOLFOX therapy in a patient-derived mouse xenograft model of colorectal cancer. Salinomycin induces apoptosis of human colorectal cancer cells, accompanied by accumulation of dysfunctional mitochondria and reactive oxygen species. These effects are associated with expressional down-regulation of superoxide dismutase-1 (SOD1) in response to salinomycin treatment.ConclusionCollectively, the results of this pre-clinical study indicate that salinomycin alone or in combination with 5-fluorouracil and oxaliplatin exerts increased antitumoral activity compared to common chemotherapy.
Highlights
Colorectal cancer is one of the most common malignancies worldwide with the fourth highest prevalence among females and males and a lifetime risk of 1 in 20 persons [1,2]
Applying tumor-initiating cells (TIC) isolated from human patients with colorectal liver metastases or from human primary colon carcinoma, we demonstrated that salinomycin exerts increased antiproliferative activity compared to 5-fluorouracil and oxaliplatin treatment
Chemotherapy is fluoropyrimidine-based combined with oxaliplatin or irinotecan and monoclonal antibodies targeting vascular endothelial growth factor (VEGF) or, in case of no KRAS mutations, endothelial growth factor receptor (EGFR)
Summary
Colorectal cancer is one of the most common malignancies worldwide with the fourth highest prevalence among females and males and a lifetime risk of 1 in 20 persons [1,2]. While the combination of radical surgical resection and neo- and/or adjuvant (radio)chemotherapy results in 5-year survival rates of 65%, metastasized colorectal cancer is associated with decreased long-time survival [3]. Effective chemotherapy in the metastasized or palliative situation is often hindered due to a small fraction of phenotypically different cells within the primary tumor, which exhibits an increased tumorigenic potential and retains resistance against chemotherapy and formation of metastases. This subpopulation of cells is commonly referred to as cancer stem cells [4]. No specific anti-cancer stem cell therapy exists
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