HAMPT, A Novel Quadruple Drug Combination Designed for Cancer Metastatic Chemoprevention: From Hypothesis to Proof-of-concept

Author(s): Huo Xu , Liyuan Wan , Jianguo Xu , Jian Liu , Ning Zheng , Lee Jia* .

Journal Name: Current Cancer Drug Targets

Volume 19 , Issue 4 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Highly Active Metastasis Preventing Therapy (HAMPT) is a quardruple drug combination consisting of mifepristone, aspirin, lysine and doxycycline.

Objective: Based on our previous study, here, we further proved that HAMPT could effectively and safely prevent colon cancer metastasis.

Methods: It was specifically designed for synergistically controlling key cancer metastatic pathways. The dose of HAMPT was designed at lower than the pharmaceutically-recommended dose, and thus the sub-healthy cancer survivors may take HAMPT safely and for a long time for metastasis chemoprevention.

Results: HAMPT within its effective concentration range (1-50 µg/mL) showed no cytotoxicity to colon cancer cells HT-29 and CT-26, but significantly inhibited adhesion and invasion of these colon cancer cell lines to human umbilical vascular endothelial cells (HUVECs), and to Matrigel. HAMPT exhibits a good adhesion inhibited ratio, suggesting that it functions primarily by inhibiting adhesion of the cancer cells to HUVECs, rather than killing the cancer cells. At low concentrations, HAMPT also inhibited cancer cell migration. Flow cytometry analysis revealed that HAMPT had no significant effect on cell cycle, but inhibited IL-1β-induced expression of both E-selectin of HUVECs and Sialyl-Lewis X of HT-29. The in vivo experiment showed that HAMPT suppressed metastasis of CT-26 cells to mouse lungs in a dose-dependent manner. In the mouse model, HAMPT showed advantages in preventing metastasis over other combinations.

Conclusion: The present study demonstrated that HAMPT is a novel quadruple drug combination that can safely and effectively prevent cancer metastasis.

Keywords: Colon cancer metastasis, drug combination, circulating tumor cells, cell adhesion molecules HAMPT, chemoprevention, quadruple drug combination.

[1]
DeSantis, C.E.; Lin, C.C.; Mariotto, A.B.; Siegel, R.L.; Stein, K.D.; Kramer, J.L.; Alteri, R.; Robbins, A.S.; Jemal, A. Cancer treatment and survivorship statistics. CA Cancer J. Clin., 2014, 64(4), 252-271.
[2]
Perret, G. Pharmacological strategies and micrometastasis: what is known? What must be done? Minerva Med., 2010, 101(3), 163-178.
[3]
Kitamura, T.; Qian, B-Z.; Soong, D.; Cassetta, L.; Noy, R.; Sugano, G.; Kato, Y.; Li, J.; Pollard, J.W. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med., 2015, 212(7), 1043-1059.
[4]
Demicheli, R.; Retsky, M.; Hrushesky, W.; Baum, M.; Gukas, I. The effects of surgery on tumor growth: A century of investigations. Ann. Oncol., 2008, mdn386.
[5]
Yu, M.; Bardia, A.; Aceto, N.; Bersani, F.; Madden, M.W.; Donaldson, M.C.; Desai, R.; Zhu, H.; Comaills, V.; Zheng, Z. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science, 2014, 345(6193), 216-220.
[6]
American Society of Clinical Oncology. The state of cancer care in America, 2014: A report by the american society of clinical oncology. J. Oncol. Pract., 2014, 10(2), 119-142.
[7]
Bottos, A.; Hynes, N.E. Cancer: Staying together on the road to metastasis. Nature, 2014, 514(7522), 309-310.
[8]
Krebs, M.G.; Renehan, A.G.; Backen, A.; Gollins, S.; Chau, I.; Hasan, J.; Valle, J.W.; Morris, K.; Beech, J.; Ashcroft, L. Circulating tumor cell enumeration in a phase II trial of a four-drug regimen in advanced colorectal cancer. Clin. Colorectal Cancer, 2015, 14(2), 115-122.
[9]
Glynn, R.J.; Seddon, J.M.; Gragoudas, E.S.; Egan, K.M.; Hart, L.J. Evaluation of tumor regression and other prognostic factors for early and late metastasis after proton irradiation of uveal melanoma. Ophthalmology, 1989, 96(10), 1566-1573.
[10]
Paterlini-Brechot, P.; Benali, N.L. Circulating tumor cells (CTC) detection: clinical impact and future directions. Cancer Lett., 2007, 253(2), 180-204.
[11]
Wang, J.; Chen, J.; Wan, L.; Shao, J.; Lu, Y.; Zhu, Y.; Ou, M.; Yu, S.; Chen, H.; Jia, L. Synthesis, spectral characterization, and in vitro cellular activities of metapristone, a potential cancer metastatic chemopreventive agent derived from mifepristone (RU486). AAPS J., 2014, 16(2), 289-298.
[12]
Eccles, S.A.; Welch, D.R. Metastasis: Recent discoveries and novel treatment strategies. Lancet, 2007, 369(9574), 1742-1757.
[13]
(a) Li, Da-Qiang Z.-B. W., Jin Bai, Jie Zhao, Yuan Wang, Kai Hu, Yong-Hong Du. Effects of mifepristone on invasive and metastatic potential of human gastric adenocarcinoma cell line MKN-45 in vitro and in vivo. World J. Gastroenterol., 2004, 10(12), 1726-1729.
(b) Yu, S.; Yang, X.; Zhu, Y.; Xie, F.; Lu, Y.; Yu, T.; Yan, C.; Shao, J.; Gao, Y.; Mo, F. Systems pharmacology of mifepristone (RU486) reveals its 47 hub targets and network: Comprehensive analysis and pharmacological focus on FAK-Src-Paxillin complex. Sci. Rep., 2015, 5.
[14]
(a) Livolsi, V.A. Anti-metastatic effect of aspirin. Lancet, 1973, 2(7783), 932.
(b) Gasic, G.J.; Gasic, T.B.; Galanti, N.; Johnson, T.; Murphy, S. Platelet-tumor-cell interactions in mice. The role of platelets in the spread of malignant disease. Int. J. Cancer, 1973, 11(3), 704-718.
[15]
(a) Van den, B.C.; Dontje, B.H.; Kroon, A.M. Arrest of in vivo growth of a solid Leydig cell tumor by prolonged inhibition of mitochondrial protein synthesis. Cancer Res., 1983, 43(5), 2247-2251.
(b) Fife, R.S.; Jr, S.G. Effects of doxycycline on in vitro growth, migration, and gelatinase activity of breast carcinoma cells. J. Lab. Clin. Med., 1995, 125(3), 407-411.
[16]
Fife, R.S.; Sledge, G.W.; Roth, B.J.; Proctor, C. Effects of doxycycline on human prostate cancer cells in vitro. Cancer Lett., 1998, 127(1), 37-41.
[17]
Rath, M. Plasmin-induced proteolysis and the role of apoprotein(a), lysine, and synthetic lysine analogs. J. Orthomol. Med., 1992, 7(1), 17-23.
[18]
Wan, L.; Dong, H.; Huo Xu, J. M.; Zhu, Y.; Lu, Y.; Wang, J.; Zhang, T.; Li, T.; Xie, J.; Xu, B. Aspirin, lysine, mifepristone and doxycycline combined can effectively and safely prevent and treat cancer metastasis: Prevent seeds from gemmating on soil. Oncotarget, 2015, 6(34), 35157-35172.
[19]
Rothwell, P.M.; Wilson, M.; Price, J.F.; Belch, J.F.; Meade, T.W.; Mehta, Z. Effect of daily aspirin on risk of cancer metastasis: A study of incident cancers during randomised controlled trials. Lancet, 2012, 379(9826), 1591-1601.
[20]
(a) Roomi, M.W.; Ivanov, V.; Kalinovsky, T.; Niedzwiecki, A.; Rath, M. In vivo antitumor effect of ascorbic acid, lysine, proline and green tea extract on human prostate cancer PC-3 xenografts in nude mice: Evaluation of tumor growth and immunohistochemistry. Vivo, 2005, 19(1), 179-183.
(b) Ibrahimhashim, A.; Wojtkowiak, J. W.; Estrella, V.; Bailey, K. M.; Cornnell, H. H.; Gatenby, R. A.; Gillies, R.J. Free base lysine increases survival and reduces metastasis in prostate cancer model.J. Cancer Sci. Ther., 2011. 4(suppl 1), JCST-S1-004
[21]
Jiang, Z.; Pang, Y.; Yu, X.; Zhou, S.; Qian, J.; Zheng, N.; Dong, H.; Shi, Q.; Kuo, M.; Jia, L. The paradigm-shifting idea and its practice: From traditional abortion Chinese medicine Murraya paniculata to safe and effective cancer metastatic chemopreventives. Oncotarget, 2016, 7(16), 21699-21712.
[22]
Lu, Y.; Yu, T.; Liang, H.; Wang, J.; Xie, J.; Shao, J.; Gao, Y.; Yu, S.; Chen, S.; Wang, L. Nitric oxide inhibits hetero-adhesion of cancer cells to endothelial cells: Restraining circulating tumor cells from initiating metastatic cascade. Sci. Rep., 2014, 4, 4344.
[23]
Shao, J.; Zhou, S.; Jiang, Z.; Chi, T.; Ma, J.; Kuo, M.; Lee, A.Y-L.; Jia, L. Warfarin and coumarin-like Murraya paniculata extract down-regulate EpCAM-mediated cell adhesion: Individual components versus mixture for studying botanical metastatic chemopreventives. Sci. Rep., 2016, 6, 30549.
[24]
Lian, S.; Lu, Y.; Cheng, Y.; Yu, T.; Xie, X.; Liang, H.; Ye, Y.; Jia, L. S-nitrosocaptopril interrupts adhesion of cancer cells to vascular endothelium by suppressing cell adhesion molecules via inhibition of the NF-кB and JAK/STAT signal pathways in endothelial cells. Eur. J. Pharmacol., 2016, 791, 62-71.
[25]
Xie, J.; Gao, Y.; Zhao, R.; Sinko, P.J.; Gu, S.; Wang, J.; Li, Y.; Lu, Y.; Yu, S.; Wang, L. Ex vivo and in vivo capture and deactivation of circulating tumor cells by dual-antibody-coated nanomaterials. J. Control. Release, 2015, 209, 159-169.
[26]
Lennox, J.L.; DeJesus, E.; Lazzarin, A.; Pollard, R.B.; Madruga, J.V.R.; Berger, D.S.; Zhao, J.; Xu, X.; Williams-Diaz, A.; Rodgers, A.J. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: A multicentre, double-blind randomised controlled trial. Lancet, 2009, 374(9692), 796-806.
[27]
(a) Rothwell, P.M.; Wilson, M.; Price, J.F.; Belch, J.F.; Meade, T.W.; Mehta, Z. Effect of daily aspirin on risk of cancer metastasis: A study of incident cancers during randomised controlled trials. Lancet, 2012, 379(9826), 1591-1601.
(b) Gay, L.J.; Felding-Habermann, B. Contribution of platelets to tumour metastasis. Nat. Rev. Cancer, 2011, 11(2), 123-134.
[28]
(a) Fife, R.S.; Rougraff, B.T.; Proctor, C.; Sledge, G.W., Jr Inhibition of proliferation and induction of apoptosis by doxycycline in cultured human osteosarcoma cells. J. Lab. Clin. Med., 1997, 130(5), 530-534.
(b) Aladakatti, S.; Patil, P.; Vivek, V. Influence of tetracyclines on inflammation and their interaction with aspirin in male Wistar rats. Pharmacol. Online, 2008, 3, 808-819.
[29]
(a) Ibrahim-Hashim, A.; Wojtkowiak, J.W.; de Lourdes Coelho Ribeiro, M.; Estrella, V.; Bailey, K.M.; Cornnell, H.H.; Gatenby, R.A.; Gillies, R.J. Free base lysine increases survival and reduces metastasis in prostate cancer model.J. Cancer Sci. Ther, 2011 (4),.
(b) Roomi, M.W.; Ivanov, V.; Kalinovsky, T.; Niedzwiecki, A.; Rath, M. In vitro and in vivo antitumorigenic activity of a mixture of lysine, proline, ascorbic acid, and green tea extract on human breast cancer lines MDA-MB-231 and MCF-7. Med. Oncol., 2005, 22(2), 129-138.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 4
Year: 2019
Page: [296 - 303]
Pages: 8
DOI: 10.2174/1568009618666181001102557
Price: $58

Article Metrics

PDF: 29
HTML: 3