# Sunitinib malate induces cell death in adult human cardiac progenitor cells

## TL;DR

Sunitinib, a cancer drug, harms heart progenitor cells by reducing their viability and causing non-apoptotic cell death.

## Contribution

The study shows sunitinib causes non-apoptotic cell death in cardiac progenitor cells at clinically relevant concentrations.

## Key findings

- Sunitinib reduced CPC viability by 26.5% at 2 μM for 24 hours.
- Sunitinib increased apoptosis-related gene and protein expression but did not induce late-stage apoptosis.
- Sunitinib accumulated in lysosomes and autophagosomes, leading to non-apoptotic cell death.

## Abstract

•Cardiac progenitor cell viability is reduced by peak and trough concentrations of sunitinib.•Sunitinib concentrates within autophagosomes and lysosomes in cardiac progenitor cells and reduces mitochondrial membrane potential.•Sunitinib increased apoptosis-associated gene and protein expression but late-stage apoptosis was not induced.

Cardiac progenitor cell viability is reduced by peak and trough concentrations of sunitinib.

Sunitinib concentrates within autophagosomes and lysosomes in cardiac progenitor cells and reduces mitochondrial membrane potential.

Sunitinib increased apoptosis-associated gene and protein expression but late-stage apoptosis was not induced.

Sunitinib malate is known to cause cardiotoxicity in a sub-population of patients, with heart failure seen in more severe cases. Cardiac progenitor cells (CPCs) have been identified in adult human myocardium and contribute to overall tissue maintenance, with previous work identifying negative impacts of sunitinib on these cells. This study aimed to characterise the toxic effects of sunitinib in human CPCs, applying sunitinib concentrations equivalent to clinical plasma levels to these cells in vitro. Cell viability was reduced by 26.5 ± 6.6 % by 2 μM sunitinib for 24 h (p < 0.01); this concentration also induced fold-change increases in gene expression of: calpain (3.1 ± 0.73, p < 0.05), FAS (2.3 ± 0.8, p < 0.05) and BAX (1.9 ± 0.2, p < 0.05), and a decrease in BCL-2 (3.5 ± 0.0, p < 0.001), vs. control (1.0 ± 0.0). This was affirmed by sunitinib inducing fold changes in protein expression of: calpain-1 (2.5 ± 0.5, p < 0.05); FAS receptor (2.1 ± 0.2, p < 0.05) and BAX (2.1 ± 0.2, p < 0.05) vs. control (1.0 ± 0.0). These results indicated that sunitinib induced apoptosis in CPCs, but negative annexin V staining and lack of protection by caspase inhibitors indicated this was not the cell death pathway activated. Further investigation found sunitinib was concentrated in the lysosomes and autophagosomes within CPCs, but did not induce accumulation of acidic organelles. In conclusion, these data confirm that cell death is caused by sunitinib in CPCs at concentrations equivalent to clinical plasma levels, inducing cell death pathway signals that lead to non-apoptotic cell death.