Combination of lactate calcium salt with 5‑indanesulfonamide and α‑cyano‑4‑hydroxycinnamic acid to enhance the antitumor effect on HCT116 cells via intracellular acidification

Jeong,Keun‑Yeong; Mander,Poonam; Sim,Jae Jun; Kim,Hwan Mook

doi:10.3892/ol.2016.4137

Combination of lactate calcium salt with 5‑indanesulfonamide and α‑cyano‑4‑hydroxycinnamic acid to enhance the antitumor effect on HCT116 cells via intracellular acidification

Authors:
- Keun‑Yeong Jeong
- Poonam Mander
- Jae Jun Sim
- Hwan Mook Kim
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Affiliations: College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 406‑840, Republic of Korea
Published online on: January 20, 2016 https://doi.org/10.3892/ol.2016.4137
Pages: 1866-1872

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Abstract

Maintenance of a neutral intracellular pH (pHi) is favorable for the survival of tumors, and maintenance of highly acidic extracellular pH (pHe) facilitates tumor invasiveness. The aim of the present study was to investigate the antitumor effects of lactate calcium salt (CaLa), 5‑indanesulfonamide (IS) and α‑cyano‑4‑hydroxycinnamic acid (CA) via pH regulation in colon cancer cells. HCT116 cells were treated with CaLa, IS, CA and combinations of the three. Subsequently, the concentration of intracellular lactate was determined. pHi and pHe were measured using cell lysates and culture media. Colony formation assay, cell viability assay and western blot analysis were additionally performed to analyze the consequences of the pH changes. CaLa, IS, CA and combination treatments induced an increase in the concentration of intracellular lactate. Lactate influx into the tumor microenvironment produced an acidic pHi in colon cancer cells. Consequently, colony formation and cell viability were significantly decreased, as well as poly(adenosine diphosphate‑ribose) polymerase degradation. The tumor microenvironment may be exploited therapeutically by disrupting the mechanism that regulates pHi, leading to cell apoptosis. The present study indicated that treatment with CaLa, IS and CA induced intracellular acidification via lactate influx, causing apoptosis of colon cancer cells. Additionally, the findings suggested that the combination of CaLa with IS and CA may enhance antitumor activity, and may provide a potential therapeutic approach for the treatment of colon cancer.

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1	Siegel R, Desantis C and Jemal A: Colorectal cancer statistics, 2014. CA Cancer J Clin. 64:104–117. 2014. View Article : Google Scholar : PubMed/NCBI
2	Benito M and Díaz-Rubio E: Molecular biology in colorectal cancer. Clin Transl Oncol. 8:391–398. 2006. View Article : Google Scholar : PubMed/NCBI
3	Parks SK, Chiche J and Pouyssegur J: pH control mechanisms of tumor survival and growth. J Cell Physiol. 226:299–308. 2011. View Article : Google Scholar : PubMed/NCBI
4	Swietach P, Patiar S, Supuran CT, Harris AL and Vaughan-Jones RD: The role of carbonic anhydrase 9 in regulating extracellular and intracellular pH in three-dimensional tumor cell growths. J Biol Chem. 284:20299–20310. 2009. View Article : Google Scholar : PubMed/NCBI
5	Doherty JR and Cleveland JL: Targeting lactate metabolism for cancer therapeutics. J Clin Invest. 123:3685–3692. 2013. View Article : Google Scholar : PubMed/NCBI
6	Semenza GL: Tumor metabolism: Cancer cells give and take lactate. J Clin Invest. 118:3835–3837. 2008.PubMed/NCBI
7	Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A, Maeda T and Baba Y: Acidic extracellular microenvironment and cancer. Cancer Cell Int. 13:892013. View Article : Google Scholar : PubMed/NCBI
8	Swietach P, Vaughan-Jones RD and Harris AL: Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev. 26:299–310. 2007. View Article : Google Scholar : PubMed/NCBI
9	McDonald PC, Winum JY, Supuran CT and Dedhar S: Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget. 3:84–97. 2012. View Article : Google Scholar : PubMed/NCBI
10	Gu MJ and Kwon KW: Carbonic anhydrase IX expression is associated with favorable prognostic factors in small intestinal carcinoma. J Histochem Cytochem. 62:205–210. 2014. View Article : Google Scholar : PubMed/NCBI
11	McIntyre A, Patiar S, Wigfield S, Li JL, Ledaki I, Turley H, Leek R, Snell C, Gatter K, Sly WS, et al: Carbonic anhydrase IX promotes tumor growth and necrosis in vivo and inhibition enhances anti-VEGF therapy. Clin Cancer Res. 18:3100–3111. 2012. View Article : Google Scholar : PubMed/NCBI
12	Dubois L, Peeters S, Lieuwes NG, Geusens N, Thiry A, Wigfield S, Carta F, McIntyre A, Scozzafava A, Dogné JM, et al: Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation. Radiother Oncol. 99:424–431. 2011. View Article : Google Scholar : PubMed/NCBI
13	Chiche J, Ilc K, Laferrière J, Trottier E, Dayan F, Mazure NM, Brahimi-Horn MC and Pouysségur J: Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res. 69:358–368. 2009. View Article : Google Scholar : PubMed/NCBI
14	Nguyen TT and Bonanno JA: Bicarbonate, NBCe1, NHE, and carbonic anhydrase activity enhance lactate-H+ transport in bovine corneal endothelium. Invest Ophthalmol Vis Sci. 52:8086–8093. 2011. View Article : Google Scholar : PubMed/NCBI
15	Nakayama Y, Torigoe T, Inoue Y, Minagawa N, Izumi H, Kohno K and Yamaguchi K: Prognostic significance of monocarboxylate transporter 4 expression in patients with colorectal cancer. Exp Ther Med. 3:25–30. 2012.PubMed/NCBI
16	Dimmer KS, Friedrich B, Lang F, Deitmer JW and Bröer S: The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem J. 350:219–227. 2000. View Article : Google Scholar : PubMed/NCBI
17	Gotanda Y, Akagi Y, Kawahara A, Kinugasa T, Yoshida T, Ryu Y, Shiratsuchi I, Kage M and Shirouzu K: Expression of monocarboxylate transporter (MCT)-4 in colorectal cancer and its role: MCT4 contributes to the growth of colorectal cancer with vascular endothelial growth factor. Anticancer Res. 33:2941–2947. 2013.PubMed/NCBI
18	Hussien R and Brooks GA: Mitochondrial and plasma membrane lactate transporter and lactate dehydrogenase isoform expression in breast cancer cell lines. Physiol Genomics. 43:255–264. 2011. View Article : Google Scholar : PubMed/NCBI
19	Lou Y, McDonald PC, Oloumi A, Chia S, Ostlund C, Ahmadi A, Kyle A, dem Keller Auf U, Leung S, Huntsman D, et al: Targeting tumor hypoxia: Suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res. 71:3364–3376. 2011. View Article : Google Scholar : PubMed/NCBI
20	Pacchiano F, Carta F, McDonald PC, Lou Y, Vullo D, Scozzafava A, Dedhar S and Supuran CT: Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J Med Chem. 54:1896–1902. 2011. View Article : Google Scholar : PubMed/NCBI
21	Draoui N and Feron O: Lactate shuttles at a glance: From physiological paradigms to anti-cancer treatments. Dis Model Mech. 4:727–732. 2011. View Article : Google Scholar : PubMed/NCBI
22	Zheng J: Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). Oncol Lett. 4:1151–1157. 2012.PubMed/NCBI
23	Touisni N, Maresca A, McDonald PC, Lou Y, Scozzafava A, Dedhar S, Winum JY and Supuran CT: Glycosyl coumarin carbonic anhydrase IX and XII inhibitors strongly attenuate the growth of primary breast tumors. J Med Chem. 54:8271–8277. 2011. View Article : Google Scholar : PubMed/NCBI
24	Klier M, Andes FT, Deitmer JW and Becker HM: Intracellular and extracellular carbonic anhydrases cooperate non-enzymatically to enhance activity of monocarboxylate transporters. J Biol Chem. 289:2765–2775. 2014. View Article : Google Scholar : PubMed/NCBI
25	Ditte Z, Ditte P, Labudova M, Simko V, Iuliano F, Zatovicova M, Csaderova L, Pastorekova S and Pastorek J: Carnosine inhibits carbonic anhydrase IX-mediated extracellular acidosis and suppresses growth of HeLa tumor xenografts. BMC Cancer. 14:3582014. View Article : Google Scholar : PubMed/NCBI
26	Lim KS, Lim KJ, Price AC, Orr BA, Eberhart CG and Bar EE: Inhibition of monocarboxylate transporter-4 depletes stem-like glioblastoma cells and inhibits HIF transcriptional response in a lactate-independent manner. Oncogene. 33:4433–4441. 2014. View Article : Google Scholar : PubMed/NCBI
27	Kim MY, Zhang T and Kraus WL: Poly(ADP-ribosyl)ation by PARP-1: ‘PAR-laying’ NAD+ into a nuclear signal. Genes Dev. 19:1951–1967. 2005. View Article : Google Scholar : PubMed/NCBI
28	Zanke BW, Lee C, Arab S and Tannock IF: Death of tumor cells after intracellular acidification is dependent on stress-activated protein kinases (SAPK/JNK) pathway activation and cannot be inhibited by Bcl-2 expression or interleukin 1beta-converting enzyme inhibition. Cancer Res. 58:2801–2808. 1998.PubMed/NCBI
29	Lagadic-Gossmann D, Huc L and Lecureur V: Alterations of intracellular pH homeostasis in apoptosis: Origins and roles. Cell Death Diff. 11:953–961. 2004. View Article : Google Scholar
30	Thammasit P, Sangboonruang S, Suwanpairoj S, Khamaikawin W, Intasai N, Kasinrerk W, Tayapiwatana C and Tragoolpua K: Intracellular Acidosis promotes mitochondrial apoptosis pathway: Role of EMMPRIN down-regulation via specific single-chain Fv intrabody. J Cancer. 6:276–286. 2015. View Article : Google Scholar : PubMed/NCBI