![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 62, Issue 3, 529-538, September 2002
Departments of Medicine (Y.-H.L.) and Oncology (R.P.-S.), Albert
Einstein College of Medicine, Bronx, New York; Department of Medicine,
Mount Sinai School of Medicine, New York, New York (J.-D.J., J.F.H.);
and Institute of Medicinal Biotechnology, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing, People's Republic
of China (J.-D.J)
Arsenic trioxide (As2O3) has been found
to induce apoptosis in leukemia cell lines and clinical remissions in
patients with acute promyelocytic leukemia. In this study, we
investigated the cytotoxic effect and mechanisms of action of
As2O3 in human tumor cell lines.
As2O3 caused inhibition of cell growth
(IC50 range, 3-14 µM) in a variety of human solid tumor
cell lines, including four human non-small-cell lung cancer cell lines
(H460, H322, H520, H661), two ovarian cancer cell lines (SK-OV-03,
A2780), cervical cancer HeLa, and breast carcinoma MCF-7, as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.
Flow cytometry analysis showed that As2O3
treatment resulted in a time-dependent accumulation of cells in the
G2/M phase. We observed, using Wright-Giemsa and
4',6-diamidine-2-phenylindole-dihydrochloride staining, that
As2O3 blocked the cell cycle in mitosis. In
vitro examination revealed that As2O3 markedly
promoted tubulin polymerization without affecting GTP binding to
-tubulin. Immunocytochemical and EM studies of treated MCF-7 cells
showed that As2O3 treatment caused changes in
the cellular microtubule network and formation of polymerized
microtubules. Similar to most anti-tubulin agents, As2O3 treatment induced up-regulation of the
cyclin B1 levels and activation of p34cdc2/cyclinB1 kinase,
as well as Bcl-2 phosphorylation. Furthermore, activation of caspase-3
and -7 and cleavage of poly(ADP-ribose) polymerase and -catenin
occurred only in As2O3-induced mitotic cells,
not in interphase cells, suggesting that
As2O3-induced mitotic arrest may be a
requirement for the activation of apoptotic pathways. In addition,
As2O3 exhibited similar inhibitory effects against parental MCF-7, P-glycoprotein-overexpressing
MCF-7/doxorubicin cells, and multidrug resistance protein
(MRP)-expressing MCF-7/etoposide cells (resistance indices, 2.3 and
1.9, respectively). Similarly, As2O3 had
similar inhibitory effect against parental ovarian carcinoma A2780
cells and tubulin mutation paclitaxel-resistant cell lines PTx10 and
PTx22 (resistance indices, 0.86 and 0.93, respectively), suggesting
that its effect on tubulin polymerization and G2/M phase
arrest is distinct from that of paclitaxel. Taken together, our data
demonstrate that As2O3 has a paclitaxel-like
effect, markedly promotes tubulin polymerization, arrests cell cycle at mitosis, and induces apoptosis. In addition,
As2O3 is a poor substrate for transport by
P-glycoprotein and MRP, and non-cross-resistant with paclitaxel
resistant cell lines due to tubulin mutation, suggesting that
As2O3 may be useful for treatment of human
solid tumors, particularly in patients with paclitaxel resistance.
This article has been cited by other articles:
|
|
 |
|
  V. L. Bae-Jump, Chunxiao Zhou, J. F. Boggess, and P. A. Gehrig Arsenic Trioxide (As2O3) Inhibits Expression of Estrogen Receptor--alpha Through Regulation of the Mitogen-activated Protein Kinase (MAPK) Pathway in Endometrial Cancer Cells Reproductive Sciences, December 1, 2008; 15(10): 1011 - 1017. [Abstract] [PDF]
|
|
|
|
 |
|
 L. Mi, Z. Xiao, B. L. Hood, S. Dakshanamurthy, X. Wang, S. Govind, T. P. Conrads, T. D. Veenstra, and F.-L. Chung Covalent Binding to Tubulin by Isothiocyanates: A MECHANISM OF CELL GROWTH ARREST AND APOPTOSIS J. Biol. Chem., August 8, 2008; 283(32): 22136 - 22146. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Lee, S. M. Son, D. J. Son, S. M. Kim, T. J. Kim, S. Song, D. C. Moon, H. W. Lee, J. C. Ryu, D.-Y. Yoon, et al. Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization independent activation of the nuclear factor-{kappa}B/I{kappa}B kinase signal pathway Mol. Cancer Ther., October 1, 2007; 6(10): 2786 - 2797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. H. Han, S. Z. Kim, S. H. Kim, and W. H. Park Arsenic trioxide inhibits growth of As4.1 juxtaglomerular cells via cell cycle arrest and caspase-independent apoptosis Am J Physiol Renal Physiol, August 1, 2007; 293(2): F511 - F520. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Zykova, F. Zhu, C. Lu, L. Higgins, Y. Tatsumi, Y. Abe, A. M. Bode, and Z. Dong Lymphokine-Activated Killer T-Cell-Originated Protein Kinase Phosphorylation of Histone H2AX Prevents Arsenite-Induced Apoptosis in RPMI7951 Melanoma Cells Clin. Cancer Res., December 1, 2006; 12(23): 6884 - 6893. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wetzler, M. T. Brady, E. Tracy, Z.-R. Li, K. A. Donohue, K. L. O'Loughlin, Y. Cheng, A. Mortazavi, A. A. McDonald, P. Kunapuli, et al. Arsenic Trioxide Affects Signal Transducer and Activator of Transcription Proteins through Alteration of Protein Tyrosine Kinase Phosphorylation. Clin. Cancer Res., November 15, 2006; 12(22): 6817 - 6825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Mulligan, L. M. Greene, S. Cloonan, M. M. Mc Gee, V. Onnis, G. Campiani, C. Fattorusso, M. Lawler, D. C. Williams, and D. M. Zisterer Identification of Tubulin as the Molecular Target of Proapoptotic Pyrrolo-1,5-benzoxazepines Mol. Pharmacol., July 1, 2006; 70(1): 60 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-H. Yih, Y.-Y. Tseng, Y.-C. Wu, and T.-C. Lee Induction of Centrosome Amplification during Arsenite-Induced Mitotic Arrest in CGL-2 Cells Cancer Res., February 15, 2006; 66(4): 2098 - 2106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hosono, T. Fukao, J. Ogihara, Y. Ito, H. Shiba, T. Seki, and T. Ariga Diallyl Trisulfide Suppresses the Proliferation and Induces Apoptosis of Human Colon Cancer Cells through Oxidative Modification of {beta}-Tubulin J. Biol. Chem., December 16, 2005; 280(50): 41487 - 41493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Dilda, A. S. Don, K. M. Tanabe, V. J. Higgins, J. D. Allen, I. W. Dawes, and P. J. Hogg Mechanism of Selectivity of an Angiogenesis Inhibitor From Screening a Genome-Wide Set of Saccharomyces cerevisiae Deletion Strains J Natl Cancer Inst, October 19, 2005; 97(20): 1539 - 1547. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. McCollum, P. C. Keng, J. C. States, and M. J. McCabe Jr. Arsenite Delays Progression through Each Cell Cycle Phase and Induces Apoptosis following G2/M Arrest in U937 Myeloid Leukemia Cells J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 877 - 887. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-H. Yih, S.-W. Hsueh, W.-S. Luu, T. H. Chiu, and T.-C. Lee Arsenite induces prominent mitotic arrest via inhibition of G2 checkpoint activation in CGL-2 cells Carcinogenesis, January 1, 2005; 26(1): 53 - 63. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
