Cantharidin induces G2/M phase arrest and apoptosis in human gastric cancer SGC-7901 and BGC-823 cells

The aim of the present study was to investigate the effect of cantharidin (CTD) on human gastric cancer cells and to explore the underlying mechanisms of these effects. The human gastric cancer SGC-7901 and BGC-823 cell lines were treated with CTD. MTS assays were then employed to examine cellular proliferation, flow cytometry was used to analyze the cell cycle and apoptosis, and western blot analysis was used to determine protein expression levels. It was found that CTD inhibited the proliferation of the human gastric cancer SGC-7901 and BGC-823 cells in a dose- and time-dependent manner in vitro. CTD also induced G2/M phase arrest and cellular apoptosis in a dose-dependent manner. In addition, CTD increased the levels of p21, caspase-7, -8 and -9, activated caspase-3, poly ADP ribose polymerase and Bad, but decreased the levels of cyclin-dependent kinase 1, cyclin A and B, B-cell lymphoma-2 (Bcl-2) and Bid. The present results suggested that CTD may inhibit the proliferation of human gastric cancer SGC-7901 and BGC-823 cells in vitro by inducing G2/M phase arrest and cell apoptosis. CTD may induce cellular G2/M phase arrest by regulating cycle-associated proteins and induce apoptosis by activating a caspase cascade or regulating the Bcl-2 family proteins.

[1]  L. Moed,et al.  Cantharidin revisited: a blistering defense of an ancient medicine. , 2001, Archives of dermatology.

[2]  Olivier Hermine,et al.  Vital functions for lethal caspases , 2005, Oncogene.

[3]  I. Herr,et al.  Cellular stress response and apoptosis in cancer therapy. , 2001, Blood.

[4]  X. Fang,et al.  Apoptosis of colorectal cancer UTC116 cells induced by Cantharidinate. , 2012, Asian Pacific journal of cancer prevention : APJCP.

[5]  Yin Wu,et al.  Cantharidin reverses multidrug resistance of human hepatoma HepG2/ADM cells via down-regulation of P-glycoprotein expression. , 2008, Cancer letters.

[6]  Jai-Sing Yang,et al.  Cantharidin induces G 2 / M phase arrest and apoptosis in human colorectal cancer colo 205 cells through inhibition of CDK 1 activity and caspase-dependent signaling pathways , 2022 .

[7]  C. Wu,et al.  Cytotoxic effects of cantharidin on the growth of normal and carcinoma cells. , 2000, Toxicology.

[8]  C. Mathers,et al.  Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 , 2010, International journal of cancer.

[9]  G. Stark,et al.  Control of the G2/M transition , 2006, Molecular biotechnology.

[10]  J. Pines,et al.  Cyclins, CDKs and cancer. , 1995, Seminars in cancer biology.

[11]  Yung-Hyun Choi,et al.  Induction of G2/M arrest and apoptosis in human gastric epithelial AGS cells by aqueous extract of Agaricus blazei. , 2006, Oncology reports.

[12]  Y. Miao,et al.  Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress‐independent growth inhibition of pancreatic cancer cells through G2/M cell‐cycle arrest and apoptosis , 2010, Cancer science.

[13]  K. Park,et al.  Flavonoids Isolated from Korea Citrus aurantium L. Induce G2/M Phase Arrest and Apoptosis in Human Gastric Cancer AGS Cells , 2011, Evidence-based complementary and alternative medicine : eCAM.

[14]  M. Kizaki,et al.  Cantharidin induces apoptosis of human multiple myeloma cells via inhibition of the JAK/STAT pathway , 2008, Cancer science.

[15]  M. Kirschner,et al.  Control of mitotic transitions by the anaphase-promoting complex. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[16]  R. Honkanen Cantharidin, another natural toxin that inhibits the activity of serine/threonine protein phosphatases types 1 and 2A , 1993, FEBS letters.

[17]  G. Evan,et al.  Proliferation, cell cycle and apoptosis in cancer , 2001, Nature.

[18]  Hui-Yi Lin,et al.  Emodin induces apoptosis in human promyeloleukemic HL-60 cells accompanied by activation of caspase 3 cascade but independent of reactive oxygen species production. , 2002, Biochemical pharmacology.

[19]  M. Kirschner,et al.  Mitosis in transition , 1994, Cell.

[20]  L. Hartwell,et al.  Checkpoints: controls that ensure the order of cell cycle events. , 1989, Science.

[21]  R. Bauer,et al.  Molecular biology of cantharidin in cancer cells , 2007, Chinese medicine.

[22]  Muhammad Khan,et al.  Xanthoxyletin, a coumarin induces S phase arrest and apoptosis in human gastric adenocarcinoma SGC-7901 cells. , 2011, Asian Pacific journal of cancer prevention : APJCP.

[23]  E. Merisor,et al.  In vitro anti-proliferation/cytotoxic activity of cantharidin (Spanish Fly) and related derivatives. , 2003, The West Indian medical journal.

[24]  Kim J. Png,et al.  The effect of cantharidins on leukemic stem cells , 2009, International journal of cancer.

[25]  Der-Zen Liu,et al.  Cantharidin-induced cytotoxicity and cyclooxygenase 2 expression in human bladder carcinoma cell line. , 2006, Toxicology.

[26]  Jin Xiang,et al.  Chinese patients with gastric cancer need targeted adjuvant chemotherapy schemes. , 2012, Asian Pacific journal of cancer prevention : APJCP.

[27]  C. Thompson,et al.  The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability , 2000, Cell Death and Differentiation.

[28]  Tin Tin Su,et al.  Cell Cycle Regulation , 2007, Fly.

[29]  Jai-Sing Yang,et al.  Cantharidin induces G2/M phase arrest and apoptosis in human colorectal cancer colo 205 cells through inhibition of CDK1 activity and caspase-dependent signaling pathways. , 2011, International journal of oncology.

[30]  U. Das,et al.  Selenium-binding protein 1 may decrease gastric cellular proliferation and migration. , 2013, International journal of oncology.

[31]  M. Barbacid,et al.  To cycle or not to cycle: a critical decision in cancer , 2001, Nature reviews. Cancer.

[32]  J. Pines,et al.  Active cyclin B1–Cdk1 first appears on centrosomes in prophase , 2003, Nature Cell Biology.

[33]  U. Das,et al.  Effects of polyunsaturated fatty acids on the growth of gastric cancer cells in vitro , 2013, Lipids in Health and Disease.

[34]  T. Hsia,et al.  Cantharidin induces apoptosis in human bladder cancer TSGH 8301 cells through mitochondria-dependent signal pathways. , 2010, International journal of oncology.

[35]  R. Ferrante,et al.  Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.