Anti-cancer mechanisms of clinically acceptable colchicine concentrations on hepatocellular carcinoma.

AIMS This study was to investigate whether the clinically acceptable colchicine concentrations had anti-cancer effects on hepatocellular carcinoma (HCC) and their anti-cancer mechanisms. MAIN METHODS Two human HCC cell lines (HCC24/KMUH, HCC38/KMUH) and two human cancer-associated fibroblast (CAF) cell lines (F28/KMUH, F59/KMUH) were investigated by proliferative assay, microarray, quantitative reverse transcriptase-polymerase chain reaction, and nude mouse study using clinically acceptable colchicine concentrations. KEY FINDINGS Both 2 and 6ng/mL colchicine significantly inhibited the cellular proliferation of all cell lines tested (P<0.05). The anti-proliferative effects of colchicine on F28/KMUH, HCC24/KMUH and HCC38/KMUH cells were dose-dependent. The anti-proliferative effects of 6ng/mL colchicine on both HCC cell lines were similar to the effects of 1μg/mL epirubicin. The anti-proliferative effects of colchicine on HCC cells could be partially explained by dose-dependent up-regulations of 2 anti-proliferative genes (AKAP12, TGFB2) in these cells. TGFB2 was also up-regulated in CAFs but was not dose-dependent. Up-regulation of MX1 which can accelerate cell death was a common effect of 6ng/mL colchicine on both CAF cell lines, but 2ng/mL colchicine down-regulated MX1 in F28/KMUH cells. Nude mouse (BALB/c-nu) experiment showed that colchicine-treated mice (0.07mgcolchicine/kg/day×14days) had lower increased tumor volume ratios, slower tumor growth rates and larger percentages of tumor necrotic areas than control mice (all P<0.05). SIGNIFICANCE Clinically acceptable colchicine concentrations have anti-cancer effects on HCC. This drug has potential for the palliative treatment of HCC.

[1]  Wei Yang,et al.  Growth Differentiation Factor 15 Is Induced by Hepatitis C Virus Infection and Regulates Hepatocellular Carcinoma-Related Genes , 2011, PloS one.

[2]  Molly Kulesz-Martin,et al.  Microtubule disruption and tumor suppression by mitogen-activated protein kinase phosphatase 4. , 2007, Cancer research.

[3]  D. Ahn,et al.  Dysregulation of overexpressed IL-32α in hepatocellular carcinoma suppresses cell growth and induces apoptosis through inactivation of NF-κB and Bcl-2. , 2012, Cancer letters.

[4]  J. Lemasters,et al.  Free tubulin modulates mitochondrial membrane potential in cancer cells. , 2010, Cancer research.

[5]  Z. Cai,et al.  Decreased expression of dual-specificity phosphatase 9 is associated with poor prognosis in clear cell renal cell carcinoma , 2011, BMC Cancer.

[6]  W. Linehan,et al.  Inhibition of Tumor Cell Motility by the Interferon-inducible GTPase MxA* , 2009, Journal of Biological Chemistry.

[7]  Z. Y. Lin,et al.  Amphotericin B up‐regulates angiogenic genes in hepatocellular carcinoma cell lines , 2009, European journal of clinical investigation.

[8]  I. Gelman,et al.  Emerging Roles for SSeCKS/Gravin/AKAP12 in the Control of Cell Proliferation, Cancer Malignancy, and Barriergenesis. , 2010, Genes & cancer.

[9]  Yan Lu,et al.  An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site , 2012, Pharmaceutical Research.

[10]  A. Zhu.  Molecularly targeted therapy for advanced hepatocellular carcinoma in 2012: current status and future perspectives. , 2012, Seminars in oncology.

[11]  M. Cooper,et al.  Prereceptor regulation of glucocorticoid action by 11β‐hydroxysteroid dehydrogenase: a novel determinant of cell proliferation , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  A. Beggs,et al.  Selenoproteins and their impact on human health through diverse physiological pathways. , 2006, Physiology.

[13]  Ming‐Lung Yu,et al.  Discordant influence of amphotericin B on epirubicin cytotoxicity in primary hepatic malignant cells collected by a new primary culture technique , 2006, Journal of gastroenterology and hepatology.

[14]  D. Haffner,et al.  Colchicine Use in Children and Adolescents With Familial Mediterranean Fever: Literature Review and Consensus Statement , 2007, Pediatrics.

[15]  M. Guan,et al.  Re-Expression of AKAP12 Inhibits Progression and Metastasis Potential of Colorectal Carcinoma In Vivo and In Vitro , 2011, PloS one.

[16]  R. Ma,et al.  Methylseleninic acid restricts tumor growth in nude mice model of metastatic breast cancer probably via inhibiting angiopoietin-2 , 2012, BMC Cancer.

[17]  Zu-Yau Lin,et al.  Cancer-associated fibroblasts up-regulate CCL2, CCL26, IL6 and LOXL2 genes related to promotion of cancer progression in hepatocellular carcinoma cells. , 2012, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[18]  B. Bhattacharyya,et al.  anti-Mitotic Activity of Colchicine and the Structural Basis for Its Interaction with Tubulin , 2008 .

[19]  Chun Cheng,et al.  Tumor necrosis factor‐alpha inhibits Schwann cell proliferation by up‐regulating Src‐suppressed protein kinase C substrate expression , 2009, Journal of neurochemistry.

[20]  G. Cocco,et al.  Colchicine in clinical medicine. A guide for internists. , 2010, European journal of internal medicine.

[21]  S. Grodecka-Gazdecka,et al.  Contribution of protein kinase A and protein kinase C signalling pathways to the regulation of HSD11B2 expression and proliferation of MCF-7 cells. , 2004, Acta biochimica Polonica.

[22]  D. Kershenobich,et al.  Colchicine delays the development of hepatocellular carcinoma in patients with hepatitis virus‐related liver cirrhosis , 2006, Cancer.

[23]  A. Schroit,et al.  Plasmin-Cleaved β-2-Glycoprotein 1 Is an Inhibitor of Angiogenesis , 2007 .

[24]  J. Dranoff,et al.  Autocrine release of TGF-beta by portal fibroblasts regulates cell growth. , 2004, FEBS letters.

[25]  K. Nagata,et al.  Interferon-inducible antiviral protein MxA enhances cell death triggered by endoplasmic reticulum stress. , 2011, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[26]  K. Nagata,et al.  Stimulus-dependent and domain-dependent cell death acceleration by an IFN-inducible protein, human MxA. , 2006, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[27]  Eva Forssell-Aronsson,et al.  Specific growth rate versus doubling time for quantitative characterization of tumor growth rate. , 2007, Cancer research.

[28]  G. Koren,et al.  Colchicine poisoning: the dark side of an ancient drug , 2010, Clinical toxicology.

[29]  M. Venturini,et al.  Influence of trastuzumab on epirubicin pharmacokinetics in metastatic breast cancer patients. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[30]  J. Scherrmann,et al.  Pharmacokinetics and absolute bioavailability of colchicine after i. v. and oral administration in healthy human volunteers and elderly subjects , 2004, European Journal of Clinical Pharmacology.

[31]  S. Spechler,et al.  Sorafenib for Treatment of Hepatocellular Carcinoma: A Systematic Review , 2012, Digestive Diseases and Sciences.

[32]  W. Jusko,et al.  Oral Absorption Characteristics and Pharmacokinetics of Colchicine in Healthy Volunteers after Single and Multiple Doses , 1996, Journal of clinical pharmacology.

[33]  M. Imazio,et al.  Colchicine in Addition to Conventional Therapy for Acute Pericarditis: Results of the COlchicine for acute PEricarditis (COPE) Trial , 2005, Circulation.

[34]  M. Kanda,et al.  Identification of the a kinase anchor protein 12 (AKAP12) gene as a candidate tumor suppressor of hepatocellular carcinoma , 2012, Journal of surgical oncology.

[35]  I. Gelman,et al.  Pivotal Role of AKAP12 in the Regulation of Cellular Adhesion Dynamics: Control of Cytoskeletal Architecture, Cell Migration, and Mitogenic Signaling , 2012, Journal of signal transduction.

[36]  G. Giannelli,et al.  Tumor‐secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts , 2011, Hepatology.

[37]  A. Blom,et al.  The C4b-binding Protein-Protein S Complex Inhibits the Phagocytosis of Apoptotic Cells* , 2004, Journal of Biological Chemistry.

[38]  G. Sivakumar,et al.  Colchicine semisynthetics: chemotherapeutics for cancer? , 2013, Current medicinal chemistry.

[39]  R. Terkeltaub,et al.  High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. , 2010, Arthritis and rheumatism.

[40]  Jing He,et al.  Suppression of glypican 3 inhibits growth of hepatocellular carcinoma cells through up-regulation of TGF-β2. , 2011, Neoplasia.

[41]  Y. Adler,et al.  Colchicine for pericarditis: hype or hope? , 2009, European heart journal.

[42]  A. Blom,et al.  C4b-binding protein binds to necrotic cells and DNA, limiting DNA release and inhibiting complement activation , 2005, The Journal of experimental medicine.

[43]  L. Roberts,et al.  The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. , 2011, Seminars in cancer biology.

[44]  J. Dranoff,et al.  Autocrine release of TGF‐β by portal fibroblasts regulates cell growth , 2004 .