Salinomycin: Anti-tumor activity in a pre-clinical colorectal cancer model

Abstract

Objectives Salinomycin 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. Methods Primary 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. Results Applying 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. Conclusion Collectively, 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.

Mitochondrial Involvement in Migration, Invasion and Metastasis

“…Consistently, in vivo studies proved that salinomycin may reduce metastasis formation in mammary tumor mouse model, bladder tumor rat model and intravenous mouse tumor model (Gupta et al, 2009;Kopp et al, 2014;Qu et al, 2015). Importantly, salinomycin is able to suppress the late stages of autophagy contributing to the ROS generation and mitochondria dysfunction (Klose et al, 2019). This might explain the mechanism by which salinomycin targets mitochondrial K + /H + exchange and prevents migration, invasion and metastasis.…”

“…Salinomycin is an antibiotic from the polyether ionophores group widely used in agriculture (Managò et al, 2015). Recently, it has been revealed that it possesses anticancer properties in different types of cancer (Klose et al, 2019;Tang et al, 2011). Salinomycin may target chemoresistant tumor cells, inhibiting Wnt/β-catenin and Sonic Hedgehog signaling pathways (Managò et al, 2015).…”

Salinomycin exerts anti‐colorectal cancer activity by targeting the β‐catenin/T‐cell factor complex

“…Salinomycin was intravenously administered every second day for 3 weeks, resulting in inhibition of disease progress for months without any serious long‐term side effects (Naujokat & Steinhart, ). Salinomycin at 4 mg·kg −1 ·day −1 showed effective antitumour activity in a patient‐derived mouse xenograft model of colorectal cancer (Klose et al, ). Moreover, intraperitoneal injection of salinomycin at doses of 3 and 5 mg·kg −1 ·day −1 markedly suppressed tumour growth in human gastric cancer xenografts without causing obvious toxicities (Li et al, ).…”

“…Salinomycin at 4 mg·kg −1 ·day −1 showed effective antitumour activity in a patient-derived mouse xenograft model of colorectal cancer (Klose et al, 2019). Moreover, intraperitoneal injection of salinomycin at doses of 3 and 5 mg·kg −1 ·day −1 markedly suppressed tumour growth in human gastric cancer xenografts without causing obvious toxicities .…”

Potential Therapies Targeting Metabolic Pathways in Cancer Stem Cells

“…As an example, salinomycin (procoxacin), a polyether potassium ionophore antibiotic, targets breast and nasopharyngeal CSCs through suppression of the Wnt/β-catenin pathway [ 34 , 63 , 64 ] ( Figure 1 ). The anticancer effect of salinomycin was observed when it was used alone or combined with other drugs (5-fluorouracil and oxaliplatin) [ 65 ] ( Figure 1 ). Epigallocatechin-3-gallate (EGCG), which blocks the Wnt/β-catenin signaling pathway, showed anticancer effect against colorectal CSCs [ 66 , 67 ] ( Figure 1 ).…”