Sanguinarine suppresses growth and induces apoptosis in childhood acute lymphoblastic leukemia

Abstract

Sanguinarine (Sang), a plant-derived compound isolated from the roots of Sanguinaria canadensis was evaluated for its potential pro-apoptotic effects in precursor B acute lymphoblastic leukemia (Pre-ALL) cell lines. Treatment of 697, REH, RS4;11, and SupB15 cell lines with Sang exhibited significant inhibition of cell viability via induction of apoptotic cell death. Sang-mediated apoptosis was found to be associated with the increased expression of proapoptotic bax with concomitant decrease of Bcl-2 expression leading to depolarization of mitochondria membrane resulting in loss of mitochondrial membrane potential (MMP). The reduced MMP caused the leakage in mitochondrial membrane and release of cytochrome c into the cytosol. The cytochrome c then mediates the activation of caspase-cascade and subsequently PARP cleavage. Furthermore, pretreatment with z-VAD-FMK, a pan-caspase inhibitor, abrogated Sang-induced inhibition of cell viability, induction of apoptosis. Sang treatment also reduced the phosphorylation of AKT and suppressed the expression of a number of anti-apoptotic genes such as cIAP1, cIAP2, and XIAP. Sang mediates its anti-cancer activity by generation of reactive oxygen species (ROS) due to depletion of glutathione level in leukemic cell lines. Pretreatment of these cells with N-acetyl cysteine (NAC) prevented Sang-induced depletion of glutathione level and mitochondrial-caspase-induced apoptosis. Finally, Sang treatment of Pre-ALL cell suppressed colony formation ability of these cells suggesting Sang has an anti-leukemic potential. Altogether, our data suggest that Sang is an efficient inducer of intrinsic apoptotic cell death via generation of ROS and exhibition of anti-leukemic effect in Pre-ALL cells raises the possibility to develop Sang as a therapeutic modality for the treatment and management of Pre-ALL.

Keywords:

• Apoptosis
• pre-ALL cells
• ROS
• sanguinarine
• signaling

Acknowledgments

The authors would like to thank Queenie Fernandes and Sara Taleb for their technical help.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at http://doi.org/10.1080/10428194.2018.1494270.

Additional information

Funding

This study was supported by Medical Research Center [RP # 16354/16], Hamad Medical Corporation, Doha, and State of Qatar.