Salinomycin as a Drug for Targeting Human Cancer Stem Cells

Table 1

Salinomycin’s action against human CSCs, cancer cells and cancers.

Target class	Target demonstrated	Effects and mechanisms	Comments	References
Breast CSCs,; breast cancer cells	Human mammary epithelial cells, immortalized and transformed by retroviral expression of SV40 large T oncogene, hTERT and H-rasV12 (= HMLER cells), and subsequent knockdown of E-cadherin by short hairpin RNA interference (= HMLER-shEcad cells).; HMLER-shEcad cells display properties of breast CSCs and had undergone EMT; Human SUM159 breast cancer cells.	HMLER-shEcad cells exhibit resistance to the chemotherapeutic drugs and cytotoxic agents paclitaxel, doxorubicin, actinomycin D, campthotecin, and staurosporine.; HMLER-shEcad cells are effectively killed by salinomycin.; Salinomycin, but not paclitaxel, inhibits tumorsphere formation of HMLER-shEcad cells.; Salinomycin induces epithelial differentiation of HMLER cells.; Salinomycin inhibits tumor-seeding ability of HMLER cells in xenograft mice.; Salinomycin induces differentiation, regression, necrosis, and apoptosis of SUM159 tumors in xenograft mice.	First demonstration that salinomycin targets human CSCs.	[128]
Breast CSCs,; breast cancer cells	CD44+ CD24− ALDH1+ cells, and SOX2 and HER2 expressing cells, isolated from the human breast cancer cell line MCF-7; MCF-7 tumors in xenograft mice.	Inhibition of tumorsphere formation and cloning efficiency by salinomycin.; Elimination of ALDH1+ and SOX2 expressing breast CSCs from tumorspheres by salinomycin.; Tumor regression and depletion of breast CSCs in MCF-7 xenograft mice by salinomycin.	Enhancement of the effects of salinomycin by doxorubicin, trastuzumab, or paclitaxel.	[85, 86, 88]
AML SCs	Human promyeloblastic CD34+ CD38− KG-1a leukemia SCs (KG-1a AML SCs) expressing functional ABC transporters P-glycoprotein, ABCG2, and ABCC11.	KG-1a AML SCs exhibit resistance to apoptosis induction by cytosine arabinoside, doxorubicin, gemcitabine, 5-fluorouracil, topotecan, etoposide, or bortezomib that can be reversed by the ABC transporter inhibitor cyclosporine A.; Salinomycin induces massive apoptosis in KG-1a AML SCs, independently of cyclosporine A.; KG-1a AML SCs cannot be adapted to survive and to proliferate in the presence of apoptosis-inducing concentrations of salinomycin.; KG-1a AML SCs can readily be adapted to survive and to proliferate in the presence of initially apoptosis-inducing concentrations of doxorubicin or bortezomib.	First demonstration that salinomycin induces apoptosis and overcomes ABC transporter-mediated multidrug resistance in human CSCs.	[16]
Lung CSCs	Human lung adenocarcinoma A549 cells expressing ALDH1, Oct-4, Nanog, and Sox2.	Salinomycin inhibits tumorsphere formation and expression of Oct-4, Nanog, and Sox2 of A549 lung adenocarcinoma cancer stem-like cells.		[130]
Gastric CSCs	Human gastric cancer cells NCI-N87 and SNU-1, expressing high levels of ALDH1, Sox2, Nanog, and Nestin and displaying resistance to 5-fluorouracil and cisplatin.	Salinomycin inhibits tumorsphere formation, proliferation, and viability of NCI-N87 and SNU-1 gastric cancer stem-like cells.		[131]
Osteosarcoma CSCs	From different human osteosarcoma cell lines, osteosarcoma CSC were enriched by tumorsphere selection, chemotherapy selection, and Oct-4 and Sox2 expression.	Salinomycin inhibits tumorsphere formation, induces apoptosis in osteosarcoma CSCs, sensitizes them to conventional cytostatic drugs, and downregulates Wnt/β-catenin signaling in the cells.		[132]
Colorectal CSCs	In human colorectal HT29 and SW480 cells, subpopulations of CSCs expressing CD133 were isolated.	Salinomycin, but not oxaliplatin, inhibits the tumorsphere forming ability and the migratory and invasive capacity of the cells and reduces the proportion of CD133 CSCs in HT29 and SW480 cells.; Salinomycin, but not oxaliplatin, induces expression of E-cadherin and downregulates expression of vimentin in HT29 cells.		[129]
Squamous cell carcinoma CSCs	Human SCC9 and OCTT2 squamous cell carcinoma cells sorted in low and high E-cadherin (Ecad) expressing cells. Low Ecad expressing cells exhibit drug resistance, mesenchymal phenotype, and properties of CSCs.	Salinomycin, but not cisplatin, inhibits proliferation of low Ecad expressing cells.; Salinomycin, but not cisplatin, eliminates low Ecad and high vimentin expressing primary mesenchymal-like SCC human tumors in xenograft in mice.		[133]
Pancreatic CSCs	From different human pancreatic cancer cell lines, pancreatic CSCs were separated by virtue of its expression of CD133 using flow cytometry.	Salinomycin inhibits the growth of CD133 expressing pancreatic CSCs in tumorsphere formation assays, while gemcitabine inhibits the growth of CD133-negative non-CSCs.; Salinomycin combined with gemcitabine eliminates the engraftment of human pancreatic cancer in xenograft mice more effectively than the single agent.	First demonstration that salinomycin eliminates human cancer (pancreatic cancer) in xenograft mice more effectively when combined with a conventional cytostatic drug (gemcitabine).	[87]
Prostate CSCs,; prostate cancer cells	Prostate CSCs with ALDH-1 activity and CD44 expression were separated from human VCaP and LNCaP prostate cancer cells.	Salinomycin inhibits ALDH-1 activity and expression of CD44 in VCaP- and LNCaP-derived prostate CSCs. Salinomycin reduces the CSCs fraction in VCaP and LNCaP prostate cancer cells. Salinomycin induces generation of ROS and grothw inhibition in VCaP and LNCaP prostate cancer cells.		[134]
Multidrug, radiation and apoptosis resistant cancer cells	Human Molt-4 and Jurkat T-cell leukemia cells, Jurkat T-cell leukemia cells overexpressing Bcl-2, primary therapy refractory CD4+ T-ALL cells from patients, Namalwa Burkitt lymphoma cells, multidrug- and radiation-resistant Namalwa Burkitt lymphoma cells overexpressing; 26S proteasomes, multidrug-resistant MES-SA/Dx5 uterine sarcoma cells expressing P-glycoprotein.	Salinomycin induces massive apoptosis in the multidrug-, radiation- and apoptosis-resistant human cancer cells. Salinomycin-induced apoptosis is independent of tumor suppressor protein p53, caspase activation, the CD95/CD95 ligand system, and the proteasome.; Salinomycin fails to induce apoptosis in normal human peripheral CD4+ T lymphocytes.	First demonstration that salinomycin induces apoptosis in human cancer cells and in multidrug-, radiation- and apoptosis-resistant cancer cells.	[125]
Chronic lymphocytic leukemia (CLL) cells	Primary CLL cells obtained from 13 CLL patients.	Salinomycin induces apoptosis in human CLL cells. Salinomycin inhibits in CLL cells proximal Wnt signaling by reducing the levels of the Wnt coreceptor LRP6 and by downregulating the expression of the Wnt target genes LEF1, cyclin D1, and fibronectin.	First demonstration that salinomycin inhibits Wnt signaling in human cancer cells (CLL cells).	[126]
Human metastatic breast cancer	Triple negative invasive ductal breast carcinoma cells from subcutaneous metastases obtained by biopsy from a 40-year-old patient with metastatic (bone and subcutaneous metastasis) breast cancer, treated systemically with salinomycin intravenously.	Systemic salinomycin treatment induces apoptosis in the cells of the metastases as evidenced in biopsies by molecular histopathology.; Salinomycin treatment induces regression of metastases, partial clinical response, and decrease of the tumor markers Ca 15-3 and CEA in metastatic triple negative invasive ductal breast cancer.	First demonstration that salinomycin induces breast cancer metastasis regression in humans and has clinical activity in human metastatic breast cancer.; First demonstration that salinomycin can be safely administered intravenously in humans.; Phase I/II clinical trial in triple negative breast cancer patients envisioned to start in 2013.	[104]
Human metastatic vulvar cancer	Squamous cell carcinoma of the vulva, 82-year-old patient with locally advanced and metastatic (pelvic lymphatic metastasis) vulvar cancer, treated systemically with salinomycin intravenously.	Systemic salinomycin treatment induces tumor regression, partial clinical response, and decrease of the tumor marker SCC in advanced vulvar cancer.	Increased clinical antitumor activity of salinomycin in combination with erlotinib.	[105]