Acetyl alkannin: A promising naphthoquinone derivative for breast cancer drug development research

Abstract

Acetyl alkannin, a naphthoquinone derivative, has emerged as a promising anticancer agent for the treatment of breast cancer. This study investigated the cytotoxic effects of acetyl alkannin on various breast cancer cell lines, including MCF-7, SK-BR-3, MDA-MB-231, and MDA-MB-468, and elucidated its mechanism of action. Acetyl alkannin demonstrated potent antiproliferative activity across all tested breast cancer cell lines, with particularly high efficacy against the SK-BR-3 cell line, as evidenced by low IC₅₀ values compared to the positive control, doxorubicin (IC₅₀= 0.48 ± 0.02, 0.08 ± 0.004, respectively). Importantly, acetyl alkannin exhibited selective cytotoxicity, preserving non-cancerous cell lines such as H9c2 rat cardiomyoblast cells and MCF-10A human breast epithelial cells, highlighting its safety profile in contrast to positive control doxorubicin, which is known to cause cardiotoxicity. Mechanistic studies revealed that acetyl alkannin caused cell cycle arrest at the G1 phase, suggesting cell cycle disruption as a key mechanism of action. Notably, a significant dose-dependent increase in ROS production indicates oxidative stress as a contributing factor. However, mitochondrial membrane potential (MMP) remained unaffected, suggesting that acetyl alkannin induces cytotoxicity through a mitochondrial-independent pathway. Acetyl alkannin exhibited low caspase-3/7 activity, minimal DNA laddering, and statistically non-significant apoptosis based on Annexin V/PI staining in SK-BR-3 cells. These findings suggest that alternative cell death mechanisms, such as necroptosis, may contribute to the observed cytotoxicity, or that variations in treatment conditions, such as different concentrations or durations, could potentially enhance apoptotic responses.

Notably, acetyl alkannin maintained its cytotoxic effect in chemoresistant MDA-MB-231/BCRP cells, highlighting its potential to overcome chemoresistance.

These findings position acetyl alkannin as a promising candidate for further development as a novel anticancer agent, warranting future in vivo studies and clinical investigations to fully exploit its therapeutic potential in the treatment of breast cancer.