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Current Cancer Drug Targets

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

Selective Antitumor Effect of Shikonin Derived DMAKO-20 on Melanoma through CYP1B1

Author(s): Junqi Cui, Xiaobo Zhou, Jia Huang, Jiahua Cui* and Jun Chen*

Volume 21, Issue 3, 2021

Published on: 16 November, 2020

Page: [223 - 231] Pages: 9

DOI: 10.2174/1568009620666201116112937

Price: $65

Abstract

Background: CYP1B1 is considered as a valuable target for chemotherapy. It catalyzes the bioactivation of naphthoquinone oximes within certain cancer cell lines. However, the expression level of CYP1B1 in melanoma and the functional role regulating the activity of DMAKO-20 as a representative naphthoquinone oxime against skin carcinoma are still unknown.

Objective: We sought to examine the expression level of CYP1B1 in melanoma and explore the molecular mechanism behind the anticancer effects of DMAKO-20 in melanoma.

Methods: CYP1B1 expression levels in paraffin specimens taken from melanoma patients, and its expression levels in B16/F10 cancer cells were investigated using immunohistochemical staining. The molecular mechanisms behind DMAKO-20 activity against melanoma were investigated by using cytotoxicity, cell scratching, apoptotic, and immunoblotting assays.

Results: CYP1B1, the P450 isoform, was expressed at high levels in melanoma tissues and cultured B16/F10 cells but was undetectable in normal tissues or fibroblasts. In cell proliferation assays, the shikonin oxime DMAKO-20 exhibited potent and selective antiproliferative effects against B16/F10 melanoma cells and inhibited migration. Several mechanisms for the anticancer effects of DMAKO-20 have been identified in B16/F10 melanoma cells, including apoptosis, upregulation of mitochondrial apoptotic Bax proteins, and downregulation of anti-apoptotic Bcl-2. The results from these mechanistic investigations indicated that DMAKO-20 underwent CYP1B1-mediated metabolic activation to activate anticancer metabolites within melanoma cells.

Conclusion: DMAKO-20 exhibited a selective cytotoxic effect on melanoma cells through CYP1B1-mediated activation. Using DMAKO-20 as a lead compound, further structural optimization may provide new drug entities for the treatments of malignant skin carcinomas.

Keywords: Skin carcinoma, melanoma, shikonin, chemotherapy, cytochrome P450, pProdrug.

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[1]
Zhou, W.; Jiang, Hda.G.; Peng, Y.; Li, S.S. Comparative study on enantiomeric excess of main akannin/shikonin derivatives isolated from the roots of three endemic Boraginaceae plants in China. Biomed. Chromatogr., 2011, 25(10), 1067-1075.
[http://dx.doi.org/10.1002/bmc.1570] [PMID: 21308700]
[2]
Andújar, I.; Ríos, J.L.; Giner, R.M.; Recio, M.C. Pharmacological properties of shikonin - a review of literature since 2002. Planta Med., 2013, 79(18), 1685-1697.
[http://dx.doi.org/10.1055/s-0033-1350934] [PMID: 24155261]
[3]
Ni, F.; Huang, X.; Chen, Z.; Qian, W.; Tong, X. Shikonin exerts antitumor activity in Burkitt’s lymphoma by inhibiting C-MYC and PI3K/AKT/mTOR pathway and acts synergistically with doxorubicin. Sci. Rep., 2018, 8(1), 3317.
[http://dx.doi.org/10.1038/s41598-018-21570-z] [PMID: 29463831]
[4]
Apalla, Z.; Nashan, D.; Weller, R.B.; Castellsagué, X. Skin cancer: epidemiology, disease burden, pathophysiology, diagnosis, and therapeutic approaches. Dermatol. Ther. (Heidelb.), 2017, 7(Suppl. 1), 5-19.
[http://dx.doi.org/10.1007/s13555-016-0165-y] [PMID: 28150105]
[5]
Garbe, C.; Peris, K.; Hauschild, A.; Saiag, P.; Middleton, M.; Bastholt, L.; Grob, J.J.; Malvehy, J.; Newton-Bishop, J.; Stratigos, A.J.; Pehamberger, H.; Eggermont, A.M. European Dermatology Forum (EDF); European Association of Dermato-Oncology (EADO); European Organisation for Research and Treatment of Cancer (EORTC). Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline - Update 2016. Eur. J. Cancer, 2016, 63, 201-217.
[http://dx.doi.org/10.1016/j.ejca.2016.05.005] [PMID: 27367293]
[6]
Swetter, S.M.; Tsao, H.; Bichakjian, C.K.; Curiel-Lewandrowski, C.; Elder, D.E.; Gershenwald, J.E.; Guild, V.; Grant-Kels, J.M.; Halpern, A.C.; Johnson, T.M.; Sober, A.J.; Thompson, J.A.; Wisco, O.J.; Wyatt, S.; Hu, S.; Lamina, T. Guidelines of care for the management of primary cutaneous melanoma. J. Am. Acad. Dermatol., 2019, 80(1), 208-250.
[http://dx.doi.org/10.1016/j.jaad.2018.08.055] [PMID: 30392755]
[7]
Eggermont, A.M.M.; Spatz, A.; Robert, C. Cutaneous Melanoma.The Lancet; , 2014.
[http://dx.doi.org/10.1016/S0140-6736(13)60802-8]
[8]
Espenel, S.; Vallard, A.; Rancoule, C.; Garcia, M.A.; Guy, J.B.; Chargari, C.; Deutsch, E.; Magné, N. Melanoma: Last call for radiotherapy. Crit. Rev. Oncol. Hematol., 2017, 110, 13-19.
[http://dx.doi.org/10.1016/j.critrevonc.2016.12.003] [PMID: 28109401]
[9]
Katlinskaya, Y.V.; Katlinski, K.V.; Yu, Q.; Ortiz, A.; Beiting, D.P.; Brice, A.; Davar, D.; Sanders, C.; Kirkwood, J.M.; Rui, H.; Xu, X.; Koumenis, C.; Diehl, J.A.; Fuchs, S.Y. Suppression of Type I Interferon Signaling Overcomes Oncogene-Induced Senescence and Mediates Melanoma Development and Progression. Cell Rep., 2016, 15(1), 171-180.
[http://dx.doi.org/10.1016/j.celrep.2016.03.006] [PMID: 27052162]
[10]
Weber, J.; Mandala, M.; Del Vecchio, M.; Gogas, H.J.; Arance, A.M.; Cowey, C.L.; Dalle, S.; Schenker, M.; Chiarion-Sileni, V.; Marquez-Rodas, I.; Grob, J.J.; Butler, M.O.; Middleton, M.R.; Maio, M.; Atkinson, V.; Queirolo, P.; Gonzalez, R.; Kudchadkar, R.R.; Smylie, M.; Meyer, N.; Mortier, L.; Atkins, M.B.; Long, G.V.; Bhatia, S.; Lebbé, C.; Rutkowski, P.; Yokota, K.; Yamazaki, N.; Kim, T.M.; de Pril, V.; Sabater, J.; Qureshi, A.; Larkin, J.; Ascierto, P.A. CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med., 2017, 377(19), 1824-1835.
[http://dx.doi.org/10.1056/NEJMoa1709030] [PMID: 28891423]
[11]
Wang, R.; Yin, R.; Zhou, W.; Xu, D.; Li, S. Shikonin and its derivatives: a patent review. Expert Opin. Ther. Pat., 2012, 22(9), 977-997.
[http://dx.doi.org/10.1517/13543776.2012.709237] [PMID: 22834677]
[12]
Guo, C.; He, J.; Song, X.; Tan, L.; Wang, M.; Jiang, P.; Li, Y.; Cao, Z.; Peng, C. Pharmacological properties and derivatives of shikonin-A review in recent years. Pharmacol. Res., 2019, 149, 104463.
[http://dx.doi.org/10.1016/j.phrs.2019.104463] [PMID: 31553936]
[13]
Huang, G.; Zhao, H.R.; Meng, Q.Q.; Zhang, Q.J.; Dong, J.Y.; Zhu, B.Q.; Li, S.S. Synthesis and biological evaluation of sulfur- containing shikonin oxime derivatives as potential antineoplastic agents. Eur. J. Med. Chem., 2018, 143, 166-181.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.031] [PMID: 29174813]
[14]
Wang, R.; Zhang, X.; Song, H.; Zhou, S.; Li, S. Synthesis and evaluation of novel alkannin and shikonin oxime derivatives as potent antitumor agents. Bioorganic Med. Chem. Lett., 2014.
[http://dx.doi.org/10.1016/j.bmcl.2014.07.012.]
[15]
Ahmad, N.; Mukhtar, H. Cytochrome p450: a target for drug development for skin diseases. J. Invest. Dermatol., 2004, 123(3), 417-425.
[http://dx.doi.org/10.1111/j.0022-202X.2004.23307.x] [PMID: 15304077]
[16]
Cui, J.; Zhang, X.; Huang, G.; Zhang, Q.; Dong, J.; Sun, G.; Meng, Q.; Li, S. DMAKO-20 as a new multitarget anticancer prodrug activated by the tumor specific CYP1B1 enzyme. Mol. Pharm., 2019, 16(1), 409-421.
[http://dx.doi.org/10.1021/acs.molpharmaceut.8b01062] [PMID: 30481041]
[17]
Go, R.E.; Hwang, K.A.; Choi, K.C. Cytochrome P450 1 family and cancers. J. Steroid Biochem. Mol. Biol., 2015, 147, 24-30.
[http://dx.doi.org/10.1016/j.jsbmb.2014.11.003] [PMID: 25448748]
[18]
Cui, J.; Li, S. Inhibitors and prodrugs targeting CYP1: a novel approach in cancer prevention and therapy. Curr. Med. Chem., 2014, 21(5), 519-552.
[http://dx.doi.org/10.2174/09298673113206660277] [PMID: 24083611]
[19]
Lingala, S.; Cui, Y.Y.; Chen, X.; Ruebner, B.H.; Qian, X.F.; Zern, M.A.; Wu, J. Immunohistochemical staining of cancer stem cell markers in hepatocellular carcinoma. Exp. Mol. Pathol., 2010, 89(1), 27-35.
[http://dx.doi.org/10.1016/j.yexmp.2010.05.005] [PMID: 20511115]
[20]
Saini, S.; Hirata, H.; Majid, S.; Dahiya, R. Functional significance of cytochrome P450 1B1 in endometrial carcinogenesis. Cancer Res., 2009, 69(17), 7038-7045.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1691] [PMID: 19690133]
[21]
McFadyen, M.C.E.; Cruickshank, M.E.; Miller, I.D.; McLeod, H.L.; Melvin, W.T.; Haites, N.E.; Parkin, D.; Murray, G.I. Cytochrome P450 CYP1B1 over-expression in primary and metastatic ovarian cancer. Br. J. Cancer, 2001, 85(2), 242-246.
[http://dx.doi.org/10.1054/bjoc.2001.1907] [PMID: 11461084]
[22]
Kwon, Y-J.; Baek, H-S.; Ye, D-J.; Shin, S.; Kim, D.; Chun, Y-J. CYP1B1 enhances cell proliferation and metastasis through induction of EMT and activation of Wnt/β-catenin signaling via Sp1 upregulation. PLoS One, 2016, 11(3), e0151598.
[http://dx.doi.org/10.1371/journal.pone.0151598] [PMID: 26981862]
[23]
Gara, R.K.; Srivastava, V.K.; Duggal, S.; Bagga, J.K.; Bhatt, M.; Sanyal, S.; Mishra, D.P. Shikonin selectively induces apoptosis in human prostate cancer cells through the endoplasmic reticulum stress and mitochondrial apoptotic pathway. J. Biomed. Sci., 2015, 22, 26.
[http://dx.doi.org/10.1186/s12929-015-0127-1] [PMID: 25879420]
[24]
Wu, Z.; Wu, L.; Li, L.; Tashiro, S.; Onodera, S.; Ikejima, T. p53- mediated cell cycle arrest and apoptosis induced by shikonin via a caspase-9-dependent mechanism in human malignant melanoma A375-S2 cells. J. Pharmacol. Sci., 2004, 94(2), 166-176.
[http://dx.doi.org/10.1254/jphs.94.166] [PMID: 14978355]
[25]
Yang, Y.Y.; He, H.Q.; Cui, J.H.; Nie, Y.J.; Wu, Y.X.; Wang, R.; Wang, G.; Zheng, J.N.; Ye, R.D.; Wu, Q.; Li, S.S.; Qian, F. Shikonin derivative DMAKO-05 Inhibits Akt signal activation and melanoma proliferation. Chem. Biol. Drug Des., 2016, 87(6), 895-904.
[http://dx.doi.org/10.1111/cbdd.12722] [PMID: 26804061]
[26]
McFadyen, M.C.E.; Melvin, W.T.; Murray, G.I. Cytochrome P450 enzymes: novel options for cancer therapeutics. Mol. Cancer Ther., 2004, 3(3), 363-371.
[PMID: 15026557]
[27]
Kumar, S. Engineering cytochrome P450 biocatalysts for biotechnology, medicine and bioremediation. Expert Opin. Drug Metab. Toxicol., 2010, 6(2), 115-131.
[http://dx.doi.org/10.1517/17425250903431040] [PMID: 20064075]

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