Selective uveal melanoma inhibition with calcium channel blockade

Shaughnessy,Michael; Lamuraglia,Grace; Klebanov,Nikolai; Ji,Zhenyu; Rajadurai,Anpuchchelvi; Kumar,Raj; Flaherty,Keith; Tsao,Hensin

doi:10.3892/ijo.2019.4873

Selective uveal melanoma inhibition with calcium channel blockade

Authors:
- Michael Shaughnessy
- Grace Lamuraglia
- Nikolai Klebanov
- Zhenyu Ji
- Anpuchchelvi Rajadurai
- Raj Kumar
- Keith Flaherty
- Hensin Tsao
View Affiliations

Affiliations: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114-2605, USA, Department of Medicine, Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Center for Melanoma, Harvard Medical School, Boston, MA 02114-2605, USA
Published online on: September 6, 2019 https://doi.org/10.3892/ijo.2019.4873
Pages: 1090-1096
Copyright: © Shaughnessy et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Uveal malignant melanoma (UMM), the most common primary adult intraocular tumor with a marked metastatic potential, is genetically unique and has unfortunately had few treatment breakthroughs. In this study, we subjected a UMM cell line to high‑throughput library screening with 1,018 FDA‑approved compounds to identify potential UMM‑selective cytotoxic agents. Amlodipine, a dihydropyridine calcium channel blocker (CCB), ranked no. 2 and no. 8 of the most cytotoxic compounds. Thus, we further characterized the differential effects of calcium blockade on UMM and cutaneous malignant melanoma (CMM) lines in vitro using growth inhibition, cell cycle progression, apoptosis and senescence assays. Amlodipine had a significantly higher growth inhibitory potency in UMM (IC50=13.1 µM) than CMM (IC50=15.9 µM, P<0.05) lines. In 3D spherical cell culture, amlodipine treatment significantly impaired tissue volume growth in two UMM lines, but exerted no significant effects among all 3 CMM lines tested. Treatment with 10 and 20 µM amlodipine induced a significant impairment of cell cycle progression and the apoptosis of UMM lines, implicating both of these processes as mediators of the observed growth inhibition in UMM compared to CMM. On the whole, the findings of this study suggest that calcium channel blockade is a potentially effective strategy for selective uveal melanoma targeting.

View Figures

View References

1	Shields CL, Furuta M, Thangappan A, Nagori S, Mashayekhi A, Lally DR, Kelly CC, Rudich DS, Nagori AV, Wakade OA, et al: Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol. 127:989–998. 2009. View Article : Google Scholar : PubMed/NCBI
2	Chattopadhyay C, Kim DW, Gombos DS, Oba J, Qin Y, Williams MD, Esmaeli B, Grimm EA, Wargo JA, Woodman SE, et al: Uveal melanoma: From diagnosis to treatment and the science in between. Cancer. 122:2299–2312. 2016. View Article : Google Scholar : PubMed/NCBI
3	Shaughnessy M, Klebanov N and Tsao H: Clinical and therapeutic implications of melanoma genomics. J Transl Genet Genom. 2:142018.
4	Singh AD and Topham A: Incidence of uveal melanoma in the United States: 1973-1997. Ophthalmology. 110:956–961. 2003. View Article : Google Scholar : PubMed/NCBI
5	Kaliki S and Shields CL: Uveal melanoma: Relatively rare but deadly cancer. Eye (Lond). 31:241–257. 2017. View Article : Google Scholar
6	Grisanti S and Tura A: Uveal melanoma. Noncutaneous melanoma. Scott JF and Gerstenblith MR: Codon Publications; Brisbane: 2018, View Article : Google Scholar
7	Eskelin S, Pyrhönen S, Hahka-Kemppinen M, Tuomaala S and Kivelä T: A prognostic model and staging for metastatic uveal melanoma. Cancer. 97:465–475. 2003. View Article : Google Scholar : PubMed/NCBI
8	Field MG, Durante MA, Anbunathan H, Cai LZ, Decatur CL, Bowcock AM, Kurtenbach S and Harbour JW: Punctuated evolution of canonical genomic aberrations in uveal melanoma. Nat Commun. 9:1162018. View Article : Google Scholar : PubMed/NCBI
9	Augsburger JJ, Corrêa ZM and Shaikh AH: Effectiveness of treatments for metastatic uveal melanoma. Am J Ophthalmol. 148:119–127. 2009. View Article : Google Scholar : PubMed/NCBI
10	Desjardins L, Levy C, Lumbroso Le Rouic L, Cassoux N, Piperno-Neumann S, Mariani P, Servois V, Dendale R, Plancher C and Asselain B: Adjuvant intravenous therapy by fotemustine in uveal melanoma: A randomised study. Acta Ophthalmologica. Sep 15–2011.Epub ahead of print. View Article : Google Scholar
11	Komatsubara KM and Carvajal RD: Immunotherapy for the treatment of uveal melanoma: Current status and emerging therapies. Curr Oncol Rep. 19:452017. View Article : Google Scholar : PubMed/NCBI
12	Jovanovic P, Mihajlovic M, Djordjevic-Jocic J, Vlajkovic S, Cekic S and Stefanovic V: Ocular melanoma: An overview of the current status. Int J Clin Exp Pathol. 6:1230–1244. 2013.PubMed/NCBI
13	Stewart TA, Yapa KT and Monteith GR: Altered calcium signaling in cancer cells. Biochim Biophys Acta. 1848:2502–2511. 2015. View Article : Google Scholar
14	Brzozowski JS and Skelding KA: The multi-functional calcium/calmodulin stimulated protein kinase (CaMK) family: Emerging targets for anti-cancer therapeutic intervention. Pharmaceuticals (Basel). 12. pp. 122019, View Article : Google Scholar
15	Cui C, Merritt R, Fu L and Pan Z: Targeting calcium signaling in cancer therapy. Acta Pharm Sin B. 7:3–17. 2017. View Article : Google Scholar : PubMed/NCBI
16	Wang X, Liu H, Xu Y, Xie J, Zhu D, Amos CI, Fang S, Lee JE, Li X, Nan H, et al: Genetic variants in the calcium signaling pathway genes are associated with cutaneous melanoma-specific survival. Carcinogenesis. 40:279–288. 2019. View Article : Google Scholar : PubMed/NCBI
17	Nussinov R, Wang G, Tsai CJ, Jang H, Lu S, Banerjee A, Zhang J and Gaponenko V: Calmodulin and PI3K signaling in KRAS cancers. Trends Cancer. 3:214–224. 2017. View Article : Google Scholar : PubMed/NCBI
18	Maiques O, Barceló C, Panosa A, Pijuan J, Orgaz JL, Rodriguez-Hernandez I, Matas-Nadal C, Tell G, Vilella R, Fabra A, et al: T-type calcium channels drive migration/invasion in BRAFV600E melanoma cells through Snail1. Pigment Cell Melanoma Res. 31:484–495. 2018. View Article : Google Scholar : PubMed/NCBI
19	Umemura M, Baljinnyam E, Feske S, De Lorenzo MS, Xie LH, Feng X, Oda K, Makino A, Fujita T, Yokoyama U, et al: Store-operated Ca²⁺ entry (SOCE) regulates melanoma proliferation and cell migration. PLoS One. 9:e892922014. View Article : Google Scholar
20	Chen X, Wu Q, Depeille P, Chen P, Thornton S, Kalirai H, Coupland SE, Roose JP and Bastian BC: RasGRP3 mediates MAPK pathway activation in GNAQ mutant uveal melanoma. Cancer Cell. 31:685–696.e6. 2017. View Article : Google Scholar : PubMed/NCBI
21	Xie S, Naslavsky N and Caplan S: Diacylglycerol kinases in membrane trafficking. Cell Logist. 5:e1078431. 2015. View Article : Google Scholar
22	Opie LH: Pharmacological differences between calcium antagonists. Eur Heart J. 18(Suppl A): A71–A79. 1997. View Article : Google Scholar : PubMed/NCBI
23	Das A, Pushparaj C, Bahí N, Sorolla A, Herreros J, Pamplona R, Vilella R, Matias-Guiu X, Martí RM and Cantí C: Functional expression of voltage-gated calcium channels in human melanoma. Pigment Cell Melanoma Res. 25:200–212. 2012. View Article : Google Scholar : PubMed/NCBI
24	Striessnig J, Ortner NJ and Pinggera A: Pharmacology of L-type calcium channels: Novel drugs for old targets? Curr Mol Pharmacol. 8:110–122. 2015. View Article : Google Scholar : PubMed/NCBI
25	Zou J, Li Y, Fan HQ and Wang JG: Effects of dihydropyridine calcium channel blockers on oxidized low-density lipoprotein induced proliferation and oxidative stress of vascular smooth muscle cells. BMC Res Notes. 5:1682012. View Article : Google Scholar : PubMed/NCBI
26	Lee H, Kang S and Kim W: Drug repositioning for cancer therapy based on large-scale drug-induced transcriptional signatures. PLoS One. 11:e01504602016. View Article : Google Scholar : PubMed/NCBI
27	Ohba T, Watanabe H, Murakami M, Radovanovic M, Iino K, Ishida M, Tosa S, Ono K and Ito H: Amlodipine inhibits cell proliferation via PKD1-related pathway. Biochem Biophys Res Commun. 369:376–381. 2008. View Article : Google Scholar : PubMed/NCBI