Identification of a novel polyprenylated acylphloroglucinol‑derived SIRT1 inhibitor with cancer‑specific anti-proliferative and invasion-suppressing activities

Zhu,lijia; Qi,Ji; Chiao,Christine  Ya-Chi; Zhang,Qiang; Porco Jr,John  A.; Faller,douglas V.; Dai,Yan

doi:10.3892/ijo.2014.2639

Identification of a novel polyprenylated acylphloroglucinol‑derived SIRT1 inhibitor with cancer‑specific anti-proliferative and invasion-suppressing activities

Authors:
- lijia Zhu
- Ji Qi
- Christine Ya-Chi Chiao
- Qiang Zhang
- John A. Porco Jr
- douglas V. Faller
- Yan Dai
View Affiliations

Affiliations: Cancer Research Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA, Department of Chemistry, Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, Boston, MA 02215, USA
Published online on: September 3, 2014 https://doi.org/10.3892/ijo.2014.2639
Pages: 2128-2136

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

SIRT1, a class III histone deacetylase, plays a critical role in regulating cancer cell growth, migration and invasion, which makes it a potential target for cancer therapeutics. In this study, we screened derivatives of several groups of natural products and identified a novel SIRT1 inhibitor JQ-101, a synthetic derivative of the polyprenylated acylphloroglucinol (PPAP) natural products, with an IC50 for SIRT1 of 30 µM in vitro, with 5-fold higher activity for SIRT1 vs. SIRT2. Exposure of tumor cells to JQ-101 significantly enhanced acetylation of p53 and histone H4K16 at known sites of SIRT1 deacetylation, validating SIRT1 as its cellular target. JQ-101 suppressed cancer cell growth and survival by targeting SIRT1, and also exhibited selective cytotoxicity towards a panel of human tumor cell lines, while producing no toxicity in two normal human cell types at comparable concentrations. JQ-101 induced both apoptosis and cell senescence, and suppressed cancer cell invasion in vitro. In summary, we have identified JQ-101 as a new SIRT1 inhibitor which may have potential application in cancer treatment through its ability to induce tumor cell apoptosis and senescence and suppress cancer cell invasion.

View Figures

View References

1	Bordone L and Guarente L: Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol. 6:298–305. 2005. View Article : Google Scholar : PubMed/NCBI
2	Inoue T, Hiratsuka M, Osaki M and Oshimura M: The molecular biology of mammalian SIRT proteins: SIRT2 in cell cycle regulation. Cell Cycle. 6:1011–1018. 2007. View Article : Google Scholar : PubMed/NCBI
3	Saunders LR and Verdin E: Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene. 26:5489–5504. 2007. View Article : Google Scholar : PubMed/NCBI
4	Donmez G and Guarente L: Aging and disease: connections to sirtuins. Aging Cell. 9:285–290. 2010. View Article : Google Scholar : PubMed/NCBI
5	Bosch-Presegue L and Vaquero A: The dual role of sirtuins in cancer. Genes Cancer. 2:648–662. 2011. View Article : Google Scholar : PubMed/NCBI
6	Knight JR and Milner J: SIRT1, metabolism and cancer. Curr Opin Oncol. 24:68–75. 2012. View Article : Google Scholar : PubMed/NCBI
7	Chu F, Chou PM, Zheng X, Mirkin BL and Rebbaa A: Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1. Cancer Res. 65:10183–10187. 2005. View Article : Google Scholar : PubMed/NCBI
8	Kojima K, Ohhashi R, Fujita Y, et al: A role for SIRT1 in cell growth and chemoresistance in prostate cancer PC3 and DU145 cells. Biochem Biophys Res Commun. 373:423–428. 2008. View Article : Google Scholar : PubMed/NCBI
9	Lee SM, Bae JH, Kim MJ, et al: Bcr-Abl-independent imatinib-resistant K562 cells show aberrant protein acetylation and increased sensitivity to histone deacetylase inhibitors. J Pharmacol Exp Ther. 322:1084–1092. 2007. View Article : Google Scholar : PubMed/NCBI
10	Liang XJ, Finkel T, Shen DW, Yin JJ, Aszalos A and Gottesman MM: SIRT1 contributes in part to cisplatin resistance in cancer cells by altering mitochondrial metabolism. Mol Cancer Res. 6:1499–1506. 2008. View Article : Google Scholar
11	Marshall GM, Liu PY, Gherardi S, et al: SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. PLoS Genet. 7:e10021352011. View Article : Google Scholar : PubMed/NCBI
12	Suzuki K, Hayashi R, Ichikawa T, et al: SRT1720, a SIRT1 activator, promotes tumor cell migration, and lung metastasis of breast cancer in mice. Oncol Rep. 27:1726–1732. 2012.PubMed/NCBI
13	Gabr AG, Goto H, Hanibuchi M, et al: Erlotinib prevents experimental metastases of human small cell lung cancer cells with no epidermal growth factor receptor expression. Clin Exp Metastasis. 29:207–216. 2012. View Article : Google Scholar
14	Byles V, Zhu L, Lovaas JD, et al: SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis. Oncogene. 31:4619–4629. 2012. View Article : Google Scholar : PubMed/NCBI
15	Zhang Y, Zhang M, Dong H, et al: Deacetylation of cortactin by SIRT1 promotes cell migration. Oncogene. 28:445–460. 2009. View Article : Google Scholar : PubMed/NCBI
16	Nakane K, Fujita Y, Terazawa R, et al: Inhibition of cortactin and SIRT1 expression attenuates migration and invasion of prostate cancer DU145 cells. Int J Urol. 19:71–79. 2012. View Article : Google Scholar
17	Holloway KR, Calhoun TN, Saxena M, et al: SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signaling. Proc Natl Acad Sci USA. 107:9216–9221. 2010. View Article : Google Scholar : PubMed/NCBI
18	Lovaas JD, Zhu L, Chiao CY, Byles V, Faller DV and Dai Y: SIRT1 enhances matrix metalloproteinase-2 expression and tumor cell invasion in prostate cancer cells. Prostate. 73:522–530. 2013. View Article : Google Scholar : PubMed/NCBI
19	Potente M, Ghaeni L, Baldessari D, et al: SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 21:2644–2658. 2007. View Article : Google Scholar : PubMed/NCBI
20	Potente M and Dimmeler S: Emerging roles of SIRT1 in vascular endothelial homeostasis. Cell Cycle. 7:2117–2122. 2008. View Article : Google Scholar : PubMed/NCBI
21	Jang KY, Hwang SH, Kwon KS, et al: SIRT1 expression is associated with poor prognosis of diffuse large B-cell lymphoma. Am J Surg Pathol. 32:1523–1531. 2008. View Article : Google Scholar : PubMed/NCBI
22	Huffman DM, Grizzle WE, Bamman MM, et al: SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res. 67:6612–6618. 2007. View Article : Google Scholar : PubMed/NCBI
23	Zhao G, Cui J, Zhang JG, et al: SIRT1 RNAi knockdown induces apoptosis and senescence, inhibits invasion and enhances chemosensitivity in pancreatic cancer cells. Gene Ther. 18:920–928. 2011. View Article : Google Scholar : PubMed/NCBI
24	Cha EJ, Noh SJ, Kwon KS, et al: Expression of DBC1 and SIRT1 is associated with poor prognosis of gastric carcinoma. Clin Cancer Res. 15:4453–4459. 2009. View Article : Google Scholar : PubMed/NCBI
25	DiMeo TA, Anderson K, Phadke P, et al: A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer. Cancer Res. 69:5364–5373. 2009. View Article : Google Scholar
26	Lee H, Kim KR, Noh SJ, et al: Expression of DBC1 and SIRT1 is associated with poor prognosis for breast carcinoma. Hum Pathol. 42:204–213. 2011. View Article : Google Scholar : PubMed/NCBI
27	Chen J, Zhang B, Wong N, et al: Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth. Cancer Res. 71:4138–4149. 2011. View Article : Google Scholar : PubMed/NCBI
28	Kriegl L, Vieth M, Kirchner T and Menssen A: Up-regulation of c-MYC and SIRT1 expression correlates with malignant transformation in the serrated route to colorectal cancer. Oncotarget. 3:1182–1193. 2012.PubMed/NCBI
29	Tseng RC, Lee CC, Hsu HS, Tzao C and Wang YC: Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients. Neoplasia. 11:763–770. 2009.PubMed/NCBI
30	Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M and Sinclair DA: Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem. 277:45099–45107. 2002. View Article : Google Scholar : PubMed/NCBI
31	Grozinger CM, Chao ED, Blackwell HE, Moazed D and Schreiber SL: Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J Biol Chem. 276:38837–38843. 2001. View Article : Google Scholar : PubMed/NCBI
32	Heltweg B, Gatbonton T, Schuler AD, et al: Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 66:4368–4377. 2006. View Article : Google Scholar : PubMed/NCBI
33	Solomon JM, Pasupuleti R, Xu L, et al: Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol Cell Biol. 26:28–38. 2006. View Article : Google Scholar : PubMed/NCBI
34	Lain S, Hollick JJ, Campbell J, et al: Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell. 13:454–463. 2008. View Article : Google Scholar : PubMed/NCBI
35	Bedalov A, Gatbonton T, Irvine WP, Gottschling DE and Simon JA: Identification of a small molecule inhibitor of Sir2p. Proc Natl Acad Sci USA. 98:15113–15118. 2001. View Article : Google Scholar : PubMed/NCBI
36	Choi G, Lee J, Ji JY, et al: Discovery of a potent small molecule SIRT1/2 inhibitor with anticancer effects. Int J Oncol. 43:1205–1211. 2013.PubMed/NCBI
37	Lara E, Mai A, Calvanese V, et al: Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect. Oncogene. 28:781–791. 2009. View Article : Google Scholar : PubMed/NCBI
38	Suzuki T, Imai K, Nakagawa H and Miyata N: 2-Anilinobenzamides as SIRT inhibitors. ChemMedChem. 1:1059–1062. 2006. View Article : Google Scholar : PubMed/NCBI
39	Gey C, Kyrylenko S, Hennig L, et al: Phloroglucinol derivatives guttiferone G, aristoforin, and hyperforin: inhibitors of human sirtuins SIRT1 and SIRT2. Angew Chem Int Ed Engl. 46:5219–5222. 2007. View Article : Google Scholar : PubMed/NCBI
40	Zhang Y, Zhang Q, Zeng SX, Zhang Y, Mayo LD and Lu H: Inauhzin and Nutlin3 synergistically activate p53 and suppress tumor growth. Cancer Biol Ther. 13:915–924. 2012. View Article : Google Scholar : PubMed/NCBI
41	Qi J and Porco JA Jr: Rapid access to polyprenylated phloroglucinols via alkylative dearomatization-annulation: total synthesis of (+/−)-clusianone(1). J Am Chem Soc. 129:12682–12683. 2007.PubMed/NCBI
42	Mitasev B and Porco JA Jr: Manganese(III)-mediated transformations of phloroglucinols: a formal oxidative [4 + 2] cycloaddition leading to bicyclo[2.2.2]octadiones. Org Lett. 11:2285–2288. 2009.PubMed/NCBI
43	Zhang Q and Porco JA Jr: Total synthesis of (+/−)-7-epi-nemorosone. Org Lett. 14:1796–1799. 2012.
44	Biber N, Mows K and Plietker B: The total synthesis of hyper-papuanone, hyperibone L, epi-clusianone and oblongifolin A. Nat Chem. 3:938–942. 2011. View Article : Google Scholar : PubMed/NCBI
45	Vaziri H, Dessain SK, Ng Eaton E, et al: hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell. 107:149–159. 2001. View Article : Google Scholar : PubMed/NCBI
46	Noh SJ, Baek HA, Park HS, et al: Expression of SIRT1 and cortactin is associated with progression of non-small cell lung cancer. Pathol Res Pract. 209:365–370. 2013. View Article : Google Scholar : PubMed/NCBI
47	Liu T, Liu PY and Marshall GM: The critical role of the class III histone deacetylase SIRT1 in cancer. Cancer Res. 69:1702–1705. 2009. View Article : Google Scholar : PubMed/NCBI
48	Li L, Wang L, Li L, et al: Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell. 21:266–281. 2012. View Article : Google Scholar : PubMed/NCBI
49	Kalle AM, Mallika A, Badiger J, Alinakhi, Talukdar P and Sachchidanand: Inhibition of SIRT1 by a small molecule induces apoptosis in breast cancer cells. Biochem Biophys Res Commun. 401:13–19. 2010. View Article : Google Scholar : PubMed/NCBI
50	Sun Y, Sun D, Li F, et al: Downregulation of Sirt1 by antisense oligonucleotides induces apoptosis and enhances radiation sensitization in A549 lung cancer cells. Lung Cancer. 58:21–29. 2007. View Article : Google Scholar : PubMed/NCBI
51	Ota H, Tokunaga E, Chang K, et al: Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. Oncogene. 25:176–185. 2006.PubMed/NCBI
52	Huang J, Gan Q, Han L, et al: SIRT1 overexpression antagonizes cellular senescence with activated ERK/S6k1 signaling in human diploid fibroblasts. PLoS One. 3:e17102008. View Article : Google Scholar : PubMed/NCBI
53	Jang SY, Kim SY and Bae YS: p53 deacetylation by SIRT1 decreases during protein kinase CKII downregulation-mediated cellular senescence. FEBS Lett. 585:3360–3366. 2011. View Article : Google Scholar : PubMed/NCBI
54	Saxena M, Dykes SS, Malyarchuk S, Wang AE, Cardelli JA and Pruitt K: The sirtuins promote Dishevelled-1 scaffolding of TIAM1, Rac activation and cell migration. Oncogene. Dec 23–2013.(Epub ahead of print).