TY - JOUR
T1 - The alkaloid sanguinarine is effective against multidrug resistance in human cervical cells via bimodal cell death
AU - Ding, Zhihu
AU - Tang, Shou-Ching
AU - Weerasinghe, Priya
AU - Yang, Xiaolong
AU - Pater, Alan
AU - Liepins, Andrejs
N1 - Funding Information:
We thank Mr. G. Chernenko, Ms. Y. Hao, and Ms. L. Lee for excellent technical assistance. The work was supported by a National Cancer Institute of Canada grant (2734 to A.P.) with funds from the Canadian Cancer Society; Medical Research Council of Canada grants (MT-9782 and MT-10140 to A.P. and MT-13178 to A.L.); and a Canadian Institutes of Health Research (CIHR) grant (ROP-40859 to A.P.).
PY - 2002/4/15
Y1 - 2002/4/15
N2 - Sanguinarine, a benzophenanthrine alkaloid, is potentially antineoplastic through induction of cell death pathways. The development of multidrug resistance (MDR) is a major obstacle to the success of chemotherapeutic agents. The aim of this study was to investigate whether sanguinarine is effective against uterine cervical MDR and, if so, by which mechanism. The effects of treatment with sanguinarine on human papillomavirus (HPV) type 16-immortalized endocervical cells and their MDR counterpart cells were compared. Trypan blue exclusion assays and clonogenic survival assays demonstrated that MDR human cervical cells are as sensitive as their drug-sensitive parental cells to death induced by sanguinarine. Upon treatment of both types of cells with sanguinarine, two distinct concentration-dependent modes of cell death were observed. Treatment with 2.12 or 4.24μM sanguinarine induced death in most cells that was characterized as apoptosis using the criteria of cell surface blebbing, as determined by light and scanning electron microscopy, and proteolytic activation of caspase-3 and cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (PARP), as detected by Western blot analysis. However, 8.48 and 16.96μM sanguinarine caused a second mode of cell death, oncosis, distinguished by cell surface blistering, and neither caspase-3 activation nor PARP cleavage. This study provides the first evidence that sanguinarine is effective against MDR in cervical cells via bimodal cell death, which displays alternative mechanisms involving different morphologies and caspase-3 activation status.
AB - Sanguinarine, a benzophenanthrine alkaloid, is potentially antineoplastic through induction of cell death pathways. The development of multidrug resistance (MDR) is a major obstacle to the success of chemotherapeutic agents. The aim of this study was to investigate whether sanguinarine is effective against uterine cervical MDR and, if so, by which mechanism. The effects of treatment with sanguinarine on human papillomavirus (HPV) type 16-immortalized endocervical cells and their MDR counterpart cells were compared. Trypan blue exclusion assays and clonogenic survival assays demonstrated that MDR human cervical cells are as sensitive as their drug-sensitive parental cells to death induced by sanguinarine. Upon treatment of both types of cells with sanguinarine, two distinct concentration-dependent modes of cell death were observed. Treatment with 2.12 or 4.24μM sanguinarine induced death in most cells that was characterized as apoptosis using the criteria of cell surface blebbing, as determined by light and scanning electron microscopy, and proteolytic activation of caspase-3 and cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (PARP), as detected by Western blot analysis. However, 8.48 and 16.96μM sanguinarine caused a second mode of cell death, oncosis, distinguished by cell surface blistering, and neither caspase-3 activation nor PARP cleavage. This study provides the first evidence that sanguinarine is effective against MDR in cervical cells via bimodal cell death, which displays alternative mechanisms involving different morphologies and caspase-3 activation status.
KW - Alkaloid sanguinarine
KW - Apoptosis
KW - Caspase-3
KW - Multidrug-resistant cervical cells
KW - Oncosis
UR - http://www.scopus.com/inward/record.url?scp=0037090858&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037090858&partnerID=8YFLogxK
U2 - 10.1016/S0006-2952(02)00902-4
DO - 10.1016/S0006-2952(02)00902-4
M3 - Article
C2 - 11996882
AN - SCOPUS:0037090858
SN - 0006-2952
VL - 63
SP - 1415
EP - 1421
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 8
ER -