COXISTAC 12%

Indications

• Breast cancer
• Cancer stem cell targeting
• Tumor growth inhibition

Dosage

Children: Refer to BNF for Children for specific dosing information as it may vary based on the treatment context and specific patient factors.

Adults: Refer to BNF for specific dosing information as it may vary based on the treatment context and specific patient factors.

Mechanism of action

Salinomycin selectively targets breast cancer stem cells (BCSCs) by suppressing cell viability and downregulating key proteins involved in cell cycle regulation, such as cyclin D1, while promoting the accumulation of p27(kip1) in the nucleus. It inhibits the self-renewal capabilities of ALDH1-positive BCSCs and reduces the levels of transcription factors like Nanog, Oct4, and Sox2. Additionally, salinomycin affects the Wnt/beta-catenin signaling pathway, which is crucial for stem cell development and its aberrant activation in cancer.

Pharmacodynamics

Salinomycin exhibits its effects by modulating cellular pathways that influence stem cell properties, particularly in cancer cells. Its ability to suppress the growth of BCSCs suggests a targeted approach to cancer treatment, potentially limiting tumor recurrence and growth by addressing the stem cell population that often contributes to treatment resistance.

Pharmacokinetics

The pharmacokinetics of salinomycin, including absorption, distribution, metabolism, and excretion, is not well characterized in the literature. However, as an antibiotic and ionophore, it is expected to have specific distribution characteristics due to its lipophilicity, which may influence its bioavailability and overall efficacy in therapeutic applications.

Pregnancy

There is insufficient data on the use of salinomycin in pregnancy. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether salinomycin is excreted in human milk. Caution should be exercised when administering to nursing mothers.

Storage

Store in a tightly closed container, protected from light and moisture, at room temperature.

Formulations

• Powder for injection
• Oral suspension

Mechanism of action

Cancer stem cells (CSCs) play important roles in the formation, growth and recurrence of tumors, particularly following therapeutic intervention. Salinomycin has received recent attention for its ability to target breast cancer stem cells (BCSCs), but the mechanisms of action involved are not fully understood. In the present study, we sought to investigate the mechanisms responsible for salinomycin's selective targeting of BCSCs and its anti-tumor activity. Salinomycin suppressed cell viability, concomitant with the downregulation of cyclin D1 and increased p27(kip1) nuclear accumulation. Mammosphere formation assays revealed that salinomycin suppresses self-renewal of ALDH1-positive BCSCs and downregulates the transcription factors Nanog, Oct4 and Sox2. TUNEL analysis of MDA-MB-231-derived xenografts revealed that salinomycin administration elicited a significant reduction in tumor growth with a marked downregulation of ALDH1 and CD44 levels, but seemingly without the induction of apoptosis. Our findings shed further light on the mechanisms responsible for salinomycin's effects on BCSCs. Salinomycin, an antibiotic potassium ionophore, has been reported recently to act as a selective breast cancer stem cell inhibitor, but the biochemical basis for its anticancer effects is not clear. The Wnt/beta-catenin signal transduction pathway plays a central role in stem cell development, and its aberrant activation can cause cancer. In this study, we identified salinomycin as a potent inhibitor of the Wnt signaling cascade. In Wnt-transfected HEK293 cells, salinomycin blocked the phosphorylation of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and induced its degradation. Nigericin, another potassium ionophore with activity against cancer stem cells, exerted similar effects. In otherwise unmanipulated chronic lymphocytic leukemia cells with constitutive Wnt activation nanomolar concentrations of salinomycin down-regulated the expression of Wnt target genes such as LEF1, cyclin D1, and fibronectin, depressed LRP6 levels, and limited cell survival. Normal human peripheral blood lymphocytes resisted salinomycin toxicity. These results indicate that ionic changes induced by salinomycin and related drugs inhibit proximal Wnt signaling by interfering with LPR6 phosphorylation, and thus impair the survival of cells that depend on Wnt signaling at the plasma membrane.