The targeted inhibition of Hsp90 by a synthetic small molecule, DPide offers an effective treatment strategy against TNBCs

Oh,Yong  Jin; Park,Sun  You; Seo,Young  Ho

doi:10.3892/or.2018.6250

The targeted inhibition of Hsp90 by a synthetic small molecule, DPide offers an effective treatment strategy against TNBCs

Authors:
- Yong Jin Oh
- Sun You Park
- Young Ho Seo
View Affiliations

Affiliations: College of Pharmacy, Keimyung University, Daegu 704‑701, Republic of Korea
Published online on: February 7, 2018 https://doi.org/10.3892/or.2018.6250
Pages: 1775-1782

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

Triple-negative breast cancers (TNBCs) are the most aggressive and metastatic subtype of breast cancers and exhibit poor clinical outcome due to the lack of drug target receptors such as estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (Her2). The limited effectiveness of therapeutic options and the poor prognosis of TNBC patients emphasize the urgent need for identifying new therapeutic agents. In this regard, heat shock protein 90 (Hsp90) has emerged as a promising therapeutic target for the treatment of TNBCs. Hsp90 is a molecular chaperone that regulates the folding, stability, and function of many oncogenic proteins. Hence, the inhibition of Hsp90 chaperone function leads to a simultaneous blockage of multiple signaling pathways in the proliferation and survival of cancers. In the present study, we performed the design, synthesis, and biological evaluation of Hsp90 inhibitors and found that a synthetic small molecule, DPide exerted a potent anticancer activity against TNBC cell line, MDA‑MB‑231 and non‑small cell lung cancer (NSCLC) cell line, H1975 with GI50 values of 0.478 and 1.67 µM, respectively. Soft‑agar colony formation assay also revealed that DPide suppressed the anchorage‑independent growth of MDA‑MB‑231 cells. Western blot analysis indicated that the treatment of MDA‑MB‑231 cells with DPide induced the proteasomal degradation of EGFR, Her2, Met, Akt, c‑Raf, and Cdk4 and the consequent cleavage of PARP, leading to apoptotic cell death. DPide also inhibited the migration and MMP9 activity of MDA‑MB‑231 cells, suggesting that the metastatic potential of TNBCs could be suppressed by DPide. Collectively, DPide offers an effective therapeutic option for the treatment TNBCs.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Anders C and Carey LA: Understanding and treating triple-negative breast cancer. Oncology (Williston Park). 22:1233–1243. 2008.PubMed/NCBI
3	Yadav BS, Sharma SC, Chanana P and Jhamb S: Systemic treatment strategies for triple-negative breast cancer. World J Clin Oncol. 5:125–133. 2014. View Article : Google Scholar : PubMed/NCBI
4	Gajria D and Chandarlapaty S: HER2-amplified breast cancer: Mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther. 11:263–275. 2011. View Article : Google Scholar : PubMed/NCBI
5	Garcia-Becerra R, Santos N, Diaz L and Camacho J: Mechanisms of resistance to endocrine therapy in breast cancer: Focus on signaling pathways, miRNAs and genetically based resistance. Int J Mol Sci. 14:108–145. 2012. View Article : Google Scholar : PubMed/NCBI
6	Gradishar WJ, Anderson BO, Balassanian R, Blair SL, Burstein HJ, Cyr A, Elias AD, Farrar WB, Forero A, Giordano SH, et al: NCCN guidelines insights breast cancer, version 1.2016. J Natl Compr Canc Netw. 13:1475–1485. 2015. View Article : Google Scholar : PubMed/NCBI
7	Schiff R, Massarweh S, Shou J and Osborne CK: Breast cancer endocrine resistance: How growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res. 9:447S–454S. 2003.PubMed/NCBI
8	Sankhala KK, Mita MM, Mita AC and Takimoto CH: Heat shock proteins: A potential anticancer target. Curr Drug Targets. 12:2001–2008. 2011. View Article : Google Scholar : PubMed/NCBI
9	Whitesell L and Lindquist SL: HSP90 and the chaperoning of cancer. Nat Rev Cancer. 5:761–772. 2005. View Article : Google Scholar : PubMed/NCBI
10	da Silva VC and Ramos CH: The network interaction of the human cytosolic 90 kDa heat shock protein Hsp90: A target for cancer therapeutics. J Proteomics. 75:2790–2802. 2012. View Article : Google Scholar : PubMed/NCBI
11	Zhang H and Burrows F: Targeting multiple signal transduction pathways through inhibition of Hsp90. J Mol Med (Berl). 82:488–499. 2004. View Article : Google Scholar : PubMed/NCBI
12	Chiosis G, Vilenchik M, Kim J and Solit D: Hsp90: The vulnerable chaperone. Drug Discov Today. 9:881–888. 2004. View Article : Google Scholar : PubMed/NCBI
13	Mosser DD and Morimoto RI: Molecular chaperones and the stress of oncogenesis. Oncogene. 23:2907–2918. 2004. View Article : Google Scholar : PubMed/NCBI
14	Whitesell L, Mimnaugh EG, De Costa B, Myers CE and Neckers LM: Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: Essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA. 91:pp. 8324–8328. 1994; View Article : Google Scholar : PubMed/NCBI
15	Trepel J, Mollapour M, Giaccone G and Neckers L: Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer. 10:537–549. 2010. View Article : Google Scholar : PubMed/NCBI
16	Supko JG, Hickman RL, Grever MR and Malspeis L: Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol. 36:305–315. 1995. View Article : Google Scholar : PubMed/NCBI
17	Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A, Moulick K, Taldone T, Gozman A, Guo Y, et al: Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc Natl Acad Sci USA. 106:pp. 8368–8373. 2009; View Article : Google Scholar : PubMed/NCBI
18	Lundgren K, Zhang H, Brekken J, Huser N, Powell RE, Timple N, Busch DJ, Neely L, Sensintaffar JL, Yang YC, et al: BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90. Mol Cancer Ther. 8:921–929. 2009. View Article : Google Scholar : PubMed/NCBI
19	Bao R, Lai CJ, Wang DG, Qu H, Yin L, Zifcak B, Tao X, Wang J, Atoyan R, Samson M, et al: Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer. Mol Cancer Ther. 8:3296–3306. 2009. View Article : Google Scholar : PubMed/NCBI
20	Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, et al: Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydrois oindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. J Med Chem. 53:5956–5969. 2010. View Article : Google Scholar : PubMed/NCBI
21	Wang Y, Trepel JB, Neckers LM and Giaccone G: STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. Curr Opin Investig Drugs. 11:1466–1476. 2010.PubMed/NCBI
22	Eccles SA, Massey A, Raynaud FI, Sharp SY, Box G, Valenti M, Patterson L, de Haven Brandon A, Gowan S, Boxall F, et al: NVP-AUY922: A novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res. 68:2850–2860. 2008. View Article : Google Scholar : PubMed/NCBI
23	Ohkubo S, Kodama Y, Muraoka H, Hitotsumachi H, Yoshimura C, Kitade M, Hashimoto A, Ito K, Gomori A, Takahashi K, et al: TAS-116, a highly selective inhibitor of heat shock protein 90α and β, demonstrates potent antitumor activity and minimal ocular toxicity in preclinical models. Mol Cancer Ther. 14:14–22. 2015. View Article : Google Scholar : PubMed/NCBI
24	Bussenius J, Blazey CM, Aay N, Anand NK, Arcalas A, Baik T, Bowles OJ, Buhr CA, Costanzo S, Curtis JK, et al: Discovery of XL888: A novel tropane-derived small molecule inhibitor of HSP90. Bioorg Med Chem Lett. 22:5396–5404. 2012. View Article : Google Scholar : PubMed/NCBI
25	Infante JR, Weiss GJ, Jones S, Tibes R, Bauer TM, Bendell JC, Hinson JM Jr, Von Hoff DD, Burris HA III, Orlemans EO and Ramanathan RK: Phase I dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumours. Eur J Cancer. 50:2897–2904. 2014. View Article : Google Scholar : PubMed/NCBI
26	Jeong JH, Oh YJ, Lho Y, Park SY, Liu KH, Ha E and Seo YH: Targeting the entry region of Hsp90's ATP binding pocket with a novel 6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl amide. Eur J Med Chem. 124:1069–1080. 2016. View Article : Google Scholar : PubMed/NCBI
27	Jeong CH, Park HB, Jang WJ, Jung SH and Seo YH: Discovery of hybrid Hsp90 inhibitors and their anti-neoplastic effects against gefitinib-resistant non-small cell lung cancer (NSCLC). Bioorg Med Chem Lett. 24:224–227. 2014. View Article : Google Scholar : PubMed/NCBI
28	Jeong JH, Oh YJ, Kwon TK and Seo YH: Chalcone-templated Hsp90 inhibitors and their effects on gefitinib resistance in non-small cell lung cancer (NSCLC). Arch Pharm Res. 40:96–105. 2017. View Article : Google Scholar : PubMed/NCBI
29	Dai C and Sampson SB: HSF1: Guardian of proteostasis in cancer. Trends Cell Biol. 26:17–28. 2016. View Article : Google Scholar : PubMed/NCBI
30	Dechow TN, Pedranzini L, Leitch A, Leslie K, Gerald WL, Linkov I and Bromberg JF: Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc Natl Acad Sci USA. 101:pp. 10602–10607. 2004; View Article : Google Scholar : PubMed/NCBI