High-throughput cell-based compound screen identifies pinosylvin methyl ether and tanshinone IIA as inhibitors of castration-resistant prostate cancer

Kirsi Ketola, Miro Viitala, Pekka Kohonen, Vidal Fey, Zoran Culig, Olli Kallioniemi, Kristiina Iljin

Abstract


Current treatment options for castration-resistant prostate cancer (CRPC) are limited. In this study, a high-throughput screen of 4910 drugs and drug-like molecules was performed to identify antiproliferative compounds in androgen ablated prostate cancer cells. The effect of compounds on cell viability was compared in androgen ablated LNCaP prostate cancer cells and in LNCaP cells grown in presence of androgens as well as in two non-malignant prostate epithelial cells (RWPE-1 and EP156T). Validation experiments of cancer specific anti-proliferative compounds indicated pinosylvin methyl ether (PSME) and tanshinone IIA as potent inhibitors of androgen ablated LNCaP cell proliferation. PSME is a stilbene compound with no previously described antineoplastic activity whereas tanshinone IIA is currently used in cardiovascular disorders and proposed as a cancer drug. To gain insights into growth inhibitory mechanisms in CRPC, genome-wide gene expression analysis was performed in PSME- and tanshinone IIA-exposed cells. Both compounds altered the expression of genes involved in cell cycle and steroid and cholesterol biosynthesis in androgen ablated LNCaP cells. Decrease in androgen signalling was confirmed by reduced expression of androgen receptor and prostate specific antigen in PSME- or tanshinone IIA-exposed cells. Taken together, this systematic screen identified a novel anti-proliferative agent, PSME, for CRPC. Moreover, our screen confirmed tanshinone IIA as well as several other compounds as potential prostate cancer growth inhibitors also in androgen ablated prostate cancer cells. These results provide valuable starting points for preclinical and clinical studies for CRPC treatment.


Keywords


Prostate Cancer; High-throughput screen; PSME; tanshinone IIA; CRPC

References


Adeniji AO, Chen M & Penning TM 2013 AKR1C3 as a target in castrate resistant prostate cancer. J Steroid Biochem Mol Biol 137 136-149

Aragon-Ching JB 2012 Enzalutamide (formerly MDV3100) as a new therapeutic option for men with metastatic castration-resistant prostate cancer. Asian J Androl 14 805-806

Barliya T, Mandel M, Livnat T, Weinberger D & Lavie G 2011 Degradation of HIF-1alpha under hypoxia combined with induction of Hsp90 polyubiquitination in cancer cells by hypericin: a unique cancer therapy. PloS one 6 e22849

Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM & Anderson DW 2001 SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A 98 13681-13686

Berruti A, Generali D & Tampellini M 2012 Enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367 2448

Bjorkman M, Iljin K, Halonen P, Sara H, Kaivanto E, Nees M & Kallioniemi OP 2008 Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer. Int J Cancer 123 2774-2781

Brožič P, Turk S, Adeniji AO, Konc J, Janežič D, Penning TM, Lanišnik Rižner T & Gobec S 2012 Selective inhibitors of aldo-keto reductases AKR1C1 and AKR1C3 discovered by virtual screening of a fragment library. J Med Chem 55 7417-7424

Bryant JP, Wieland GD, Reichardt PB, Lewis VE & McCarthy MC 1983 Pinosylvin methyl ether deters snowshoe hare feeding on green alder. Science 222 1023-1025

Cao MR, Li Q, Liu ZL, Liu HH, Wang W, Liao XL, Pan YL & Jiang JW 2011 Harmine induces apoptosis in HepG2 cells via mitochondrial signaling pathway. Hepatobiliary Pancreat Dis Int 10 599-604

Chen Q, Chao R, Chen H, Hou X, Yan H, Zhou S, Peng W & Xu A 2005 Antitumor and neurotoxic effects of novel harmine derivatives and structure-activity relationship analysis. Int J Cancer 114 675-682

Cheng CY & Su CC 2010 Tanshinone IIA may inhibit the growth of small cell lung cancer H146 cells by up-regulating the Bax/Bcl-2 ratio and decreasing mitochondrial membrane potential. Mol Med Rep 3 645-650

Chiu TL & Su CC 2010 Tanshinone IIA induces apoptosis in human lung cancer A549 cells through the induction of reactive oxygen species and decreasing the mitochondrial membrane potential. Int J Mol Med 25 231-236

Colasanti A, Kisslinger A, Liuzzi R, Quarto M, Riccio P, Roberti G, Tramontano D & Villani F 2000 Hypericin photosensitization of tumor and metastatic cell lines of human prostate. J Photochem Photobiol B 54 103-107

Culig Z, Hoffmann J, Erdel M, Eder IE, Hobisch A, Hittmair A, Bartsch G, Utermann G, Schneider MR, Parczyk K & Klocker H 1999 Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system. Br J Cancer 81 242-251

Dai F, Chen Y, Song Y, Huang L, Zhai D, Dong Y, Lai L, Zhang T, Li D, Pang X, Liu M & Yi Z 2012 A natural small molecule harmine inhibits angiogenesis and suppresses tumour growth through activation of p53 in endothelial cells. PLoS One 7 e52162

Dhani NC, Emmenegger U, Adams L, Jongstra J, Tannock IF, Sridhar SS, Knox JJ, Day JR, Groskopf J & Joshua AM 2012 Phase II study of cytarabine in men with docetaxel-refractory, castration-resistant prostate cancer with evaluation of TMPRSS2-ERG and SPINK1 as serum biomarkers. BJU Int 110 840-845

Dhingra R, Sharma T, Singh S, Sharma S, Tomar P, Malhotra M & Bhardwaj TR 2013 Enzalutamide: A novel anti-androgen with prolonged survival rate in CRPC patients. Mini Rev Med Chem 13 1475-1486

ElAttar TM & Virji AS 1999 Modulating effect of resveratrol and quercetin on oral cancer cell growth and proliferation. Anticancer Drugs 10 187-193

Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JY & Zhang J 2004 Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5 R80

Hamid AR, Pfeiffer MJ, Verhaegh GW, Schaafsma E, Brandt A, Sweep FC, Sedelaar JP & Schalken JA 2013 Aldo-keto reductase family 1 member C3 (AKR1C3) is a biomarker and therapeutic target for castration-resistant prostate cancer. Mol Med 18 1449-1455

Hamsa TP & Kuttan G 2010 Harmine inhibits tumour specific neo-vessel formation by regulating VEGF, MMP, TIMP and pro-inflammatory mediators both in vivo and in vitro. Eur J Pharmacol 649 64-73

He T, Haapa-Paananen S, Kaminskyy VO, Kohonen P, Fey V, Zhivotovsky B, Kallioniemi O & Perälä M 2014 Inhibition of the mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase by doxorubicin and brequinar sensitizes cancer cells to TRAIL-induced apoptosis. Oncogene 33 3538-3549

Hsieh TC & Wu JM 1999 Differential effects on growth, cell cycle arrest, and induction of apoptosis by resveratrol in human prostate cancer cell lines. Exp Cell Res 249 109-115

Iljin K, Ketola K, Vainio P, Halonen P, Kohonen P, Fey V, Grafström RC, Perälä M & Kallioniemi O 2009 High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. Clin Cancer Res 15 6070-6078

Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC & Pezzuto JM 1997 Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275 218-220

Jang M & Pezzuto JM 1999 Cancer chemopreventive activity of resveratrol. Drugs Exp Clin Res 25 65-77

Jiao JW & Wen F 2011 Tanshinone IIA acts via p38 MAPK to induce apoptosis and the down-regulation of ERCC1 and lung-resistance protein in cisplatin-resistant ovarian cancer cells. Oncol Rep 25 781-788

Kennedy MA, Barrera GC, Nakamura K, Baldán A, Tarr P, Fishbein MC, Frank J, Francone OL & Edwards PA 2005 ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab 1 121-131

Li Y, Sattler R, Yang EJ, Nunes A, Ayukawa Y, Akhtar S, Ji G, Zhang PW & Rothstein JD 2011 Harmine, a natural beta-carboline alkaloid, upregulates astroglial glutamate transporter expression. Neuropharmacology 60 1168-1175

Lin J, Adam RM, Santiestevan E & Freeman MR 1999 The phosphatidylinositol 3'-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells. Cancer Res 59 2891-2897

Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, Ettinger SL, Gleave ME & Nelson CC 2008 Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 68 6407-6415

Lu R & Serrero G 1999 Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells. J Cell Physiol 179 297-304

Luo C & Laaja P 2004 Inhibitors of JAKs/STATs and the kinases: a possible new cluster of drugs. Drug Discov Today 9 268-275

Morgan WA 1995 Naphthoquinone-induced DNA damage in the absence of oxidative stress. Biochem Soc Trans 23 225S

Out R, Hoekstra M, Habets K, Meurs I, de Waard V, Hildebrand RB, Wang Y, Chimini G, Kuiper J, Van Berkel TJ & Van Eck M 2008 Combined deletion of macrophage ABCA1 and ABCG1 leads to massive lipid accumulation in tissue macrophages and distinct atherosclerosis at relatively low plasma cholesterol levels. Arterioscler Thromb Vasc Biol 28 258-264

Penning TM & Byrns MC 2009 Steroid hormone transforming aldo-keto reductases and cancer. Ann N Y Acad Sci 1155 33-42

Schrader AJ, Boegemann M, Ohlmann CH, Schnoeller TJ, Krabbe LM, Hajili T, Jentzmik F, Stoeckle M, Schrader M, Herrmann E & Cronauer MV 2014 Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol 65 30-36

Seidah NG 2013 Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia and other pathologies. Curr Pharm Des 19 3161-3172

Souchek JJ, Baine MJ, Lin C, Rachagani S, Gupta S, Kaur S, Lester K, Zheng D, Chen S, Smith L, Lazenby A, Johansson SL, Jain M & Batra SK 2014 Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation. Br J Cancer 111 1139-1149

Steele VE, Holmes CA, Hawk ET, Kopelovich L, Lubet RA, Crowell JA, Sigman CC & Kelloff GJ 1999 Lipoxygenase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prev 8 467-483

Straus MJ, Fleit JP & Engelking C 1982 Treatment of advanced prostate cancer with cyclophosphamide, doxorubicin, and methotrexate. Cancer Treat Rep 66 1797-1802

Su CC & Lin YH 2008 Tanshinone IIA down-regulates the protein expression of ErbB-2 and up-regulates TNF-alpha in colon cancer cells in vitro and in vivo. Int J Mol Med 22 847-851

Taichman RS, Loberg RD, Mehra R & Pienta KJ 2007 The evolving biology and treatment of prostate cancer. J Clin Invest 117 2351-2361

Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA & TAX 327 Investigators 2004 Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351 1502-1512

Tyagi A, Agarwal R & Agarwal C 2003 Grape seed extract inhibits EGF-induced and constitutively active mitogenic signaling but activates JNK in human prostate carcinoma DU145 cells: possible role in antiproliferation and apoptosis. Oncogene 22 1302-1316

Vaughan AM & Oram JF 2005 ABCG1 redistributes cell cholesterol to domains removable by high density lipoprotein but not by lipid-depleted apolipoproteins. J Biol Chem 280 30150-30157

Wang X, Wei Y, Yuan S, Liu G, Lu Y, Zhang J & Wang W 2005 Potential anticancer activity of tanshinone IIA against human breast cancer. Int J Cancer 116 799-807

Won SH, Lee HJ, Jeong SJ, Lee HJ, Lee EO, Jung DB, Shin JM, Kwon TR, Yun SM, Lee MH, Choi SH, Lü J & Kim SH 2010 Tanshinone IIA induces mitochondria dependent apoptosis in prostate cancer cells in association with an inhibition of phosphoinositide 3-kinase/AKT pathway. Biol Pharm Bull 33 1828-1834

Won SH, Lee HJ, Jeong SJ, Lu J & Kim SH 2012 Activation of p53 signaling and inhibition of androgen receptor mediate tanshinone IIA induced G1 arrest in LNCaP prostate cancer cells. Phytother Res 26 669-674

Xie X, Hudson JB & Guns ES 2001 Tumor-specific and photodependent cytotoxicity of hypericin in the human LNCaP prostate tumor model. Photochem Photobiol 74 221-225

Yepuru M, Wu Z, Kulkarni A, Yin F, Barrett CM, Kim J, Steiner MS, Miller DD, Dalton JT & Narayanan R 2013 Steroidogenic enzyme AKR1C3 is a novel androgen receptor-selective coactivator that promotes prostate cancer growth. Clin Cancer Res 19 5613-5625

Zhang Y, Won SH, Jiang C, Lee HJ, Jeong SJ, Lee EO, Zhang J, Ye M, Kim SH & Lü J 2012 Tanshinones from Chinese medicinal herb Danshen (Salvia miltiorrhiza Bunge) suppress prostate cancer growth and androgen receptor signaling. Pharm Res 29 1595-1608

Zhu ML, Horbinski CM, Garzotto M, Qian DZ, Beer TM & Kyprianou N 2010 Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer. Cancer Res 70 7992-8002


Full Text: PDF

Refbacks

  • There are currently no refbacks.


Copyright © 2021 Journal of Molecular Biochemistry