Research Progress on Improving the Efficiency of CDT by Exacerbating Tumor Acidification

Figures & data

Figure 1 Schematic diagram of catalytic mechanism for cancer treatment of CDT.

Figure 2 Mechanism diagram of promoting pH reduction by using of catalytic enzymes.

Figure 3 Mechanism diagram of promoting pH reduction by carrying photoacid acid.

Figure 4 Mechanism diagram of promoting pH reduction by Inhibitor of mitochondrial complex I.

Table 1 The Inhibitors for Proton Pumps

Proton Pumps		Inhibitors	Inhibition Model	Ref.
CAIX		Sulfonamide/sulfamate	Breast tumor cell lines	[^Citation67]
		U-140 [sulfonamide]	4T1 tumor /MDA-MB-231	[^Citation68]
		FC9-398A [ureidosulfamates]	TNBC	[^Citation69]
		Glycosyl coumarin	HT-29 cells	[^Citation70]
		Indanesulfonamide	HT-29 colorectal carcinoma cells	[^Citation71]
		shRNA	4T1 breast tumors	[^Citation72]
		siRNA	BT-549 cell	[^Citation73]
		Telluride containing compounds bearing the benzenesulfonamide	MDA-MB-231 cell	[^Citation74]
		Sulfonamide dicarbaboranes	-	[^Citation75]
		Saccharide-modified thiadiazole sulfonamide derivatives	HT-29	[^Citation76]
		OCT [octyl disulfamate]	MDA-MB-231 cell	[^Citation77]
		2H-benzo [e] [1,2,4] thiadiazin-3(4H)-one-1,1-dioxides (BTD)	HCT-116	[^Citation78]
		SLC-149[4-(3-(2,4-difluorophenyl)-oxoimidazolidin-1-yl) benzenesulfonamide]	MDA-MB-231 cell	[^Citation79]
		Saccharin/isoxazole and saccharin/isoxazoline hybrids	MCF-7 cell	[^Citation80]
		Oxathiino[6,5-b] pyridine 2,2-dioxides	MCF-7 cell	[^Citation81]
		2,4-dihydro-1,2,4-triazole-3-thione derivative 9c	A-498 kidney carcinoma cells	[^Citation82]
MCT	MCT1	α-cyano-4-hydroxycinnamate (CHC)	Myeloma	[^Citation83]
		AZD3965	Human lymphoma and colon carcinoma cells	[^Citation84]
	MCT1/2	AR-C155858	4T1 breast tumor cells	[^Citation85]
	MCT4	siRNA	PC3 tumor	[^Citation86]
		2-Methoxy-4-N, N-dialkyl cyanocinnamic acids	MDA-MB-231 xenograft tumor	[^Citation87]
		Diclofenac	Melanoma	[^Citation88]
		[F-18] FACH	-	[^Citation89]
NHE		Anti NHE1 siRNA	Hepatocellular carcinoma	[^Citation90]
		Amiloride	SMMC-7721 cell	[^Citation91]
		5-(N-ethyl-N-isopropyl) amiloride	HepG2 cells	[^Citation92]
		Cariporide	MDA-MB-231	[^Citation93]
		Cariporide [HOE-642]	Mouse glioms	[^Citation94]
		siRNA	Mouse glioms	[^Citation95]
		KR-33028 [4-cyano (benzo[b]thiophene-2-carbonyl) guanidine	Triple-negative breast cancer	[^Citation96]
		HMA [5- (N, N-hexamethylene)-amiloride]	MCF-7 spheroids	[^Citation97]
		DMA [5- (N, N-Dimethyl) amiloride]
		Zoniporide	Fibroblasts	[^Citation98]
		Sabiporide	Vascular smooth muscle cell	[^Citation99]
		DEPC (diethyl pyrocarbonate)	Fibroblasts	[^Citation100]
		KR-32570[5-(2-methoxy-5-chloro-5-phenyl) furan-2-yl-carbonyl] guanidine	H9C2 cells	[^Citation101]
		T-162559	CHO-K1 cells	[^Citation102]
		SL-59.1227[imidazolypiperidine]	Hamster fibroblast cell lines	[^Citation103]
		EIPA [5-(N-ethyl-N-isopropyl) amiloride]	Human myeloid K562 cells	[^Citation104]
Na^+-HCO3^− cotransporter NBCn1		shRNA	MCF-7 spheroids	[^Citation105]
		HOE 694 plus DIDS	OEC-M cells	[^Citation106]
		SITS	Human neutrophils	[^Citation107]
		S0859(N- cyanosulphonamide compound)	HEK cell	[^Citation108]
			Glia-like progenitor cells	[^Citation109]

Figure 5 Mechanism of H⁺ transport by various proton pumps.

Figure 6 Schematic diagram of self-enhanced CDT via CAI.

Figure 7 Anticancer mechanism of MCT 4.

Bozdag M, Ferraroni M, Ward C, et al. Carbonic anhydrase inhibitors based on sorafenib scaffold: design, synthesis, crystallographic investigation and effects on primary breast cancer cells. Eur J Med Chem. 2019;182:111600. doi:10.1016/j.ejmech.2019.111600

 PubMed Web of Science ®Google Scholar

Lou Y, McDonald PC, Oloumi A, Chia S, Ostlund C, Ahmadi A. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res. 2011;71(13):4733.

 Web of Science ®Google Scholar

Williams KJ, Gieling RG. Preclinical evaluation of ureidosulfamate carbonic anhydrase IX/XII inhibitors in the treatment of cancers. Int J Mol Sci. 2019;20:23. doi:10.3390/ijms20236080

 Web of Science ®Google Scholar

Kurt BZ, Sonmez F, Ozturk D, Akdemir A, Angeli A, Supuran CT. Synthesis of coumarin-sulfonamide derivatives and determination of their cytotoxicity, carbonic anhydrase inhibitory and molecular docking studies. Eur J Med Chem. 2019;183. doi:10.1016/j.ejmech.2018.11.064

 PubMed Web of Science ®Google Scholar

Ni K, Lan G, Song Y, Hao Z, Lin W. Biomimetic nanoscale metal-organic framework harnesses hypoxia for effective cancer radiotherapy and immunotherapy. Chem Sci. 2020;11(29):7641–7653. doi:10.1039/D0SC01949F

 PubMed Web of Science ®Google Scholar

Lou Y, McDonald PC, Oloumi A, et al. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res. 2011;71(9):3364–3376. doi:10.1158/0008-5472.CAN-10-4261

 PubMed Web of Science ®Google Scholar

Sarnella A, D’Avino G, Hill BS, et al. A novel inhibitor of carbonic anhydrases prevents hypoxia-induced TNBC cell plasticity. Int J Mol Sci. 2020;21(21):8405. doi:10.3390/ijms21218405

 PubMed Web of Science ®Google Scholar

Angeli A, Pinteala M, Maier SS, et al. Tellurides bearing benzensulfonamide as carbonic anhydrase inhibitors with potent antitumor activity. Bioorg Med Chem Lett. 2021;45:128147. doi:10.1016/j.bmcl.2021.128147

 PubMed Web of Science ®Google Scholar

Kugler M, Holub J, Brynda J, et al. The structural basis for the selectivity of sulfonamido dicarbaboranes toward cancer-associated carbonic anhydrase IX. J Enzym Inhib Med Ch. 2020;35(1):1800–1810. doi:10.1080/14756366.2020.1816996

 PubMed Web of Science ®Google Scholar

Zhang ZP, Zhong Y, Han ZB, et al. Synthesis, molecular docking analysis and biological evaluations of saccharide-modified thiadiazole sulfonamide derivatives. Int J Mol Sci. 2021;22(11). doi:10.3390/ijms222413610

 Web of Science ®Google Scholar

Petrenko M, Guttler A, Funtan A, et al. Combined 3-O-acetylbetulin treatment and carbonic anhydrase IX inhibition results in additive effects on human breast cancer cells. Chem Biol Interact. 2021;4:333.

 Google Scholar

Bua S, Lomelino C, Murray AB, et al. “A sweet combination”: developing saccharin and acesulfame K structures for selectively targeting the tumor-associated carbonic anhydrases IX and XII. J Med Chem. 2020;63(1):321–333. doi:10.1021/acs.jmedchem.9b01669

 PubMed Web of Science ®Google Scholar

Mboge MY, Combs J, Singh S, et al. Inhibition of carbonic anhydrase using SLC-149: support for a noncatalytic function of CAIX in breast cancer. J Med Chem. 2021;64(3):1713–1724. doi:10.1021/acs.jmedchem.0c02077

 PubMed Web of Science ®Google Scholar

D’Ascenzio M, Secci D, Carradori S, et al. 1,3-Dipolar Cycloaddition, HPLC enantioseparation, and docking studies of saccharin/isoxazole and saccharin/isoxazoline derivatives as selective carbonic anhydrase IX and XII inhibitors. J Med Chem. 2020;63(5):2470–2488. doi:10.1021/acs.jmedchem.9b01434

 PubMed Web of Science ®Google Scholar

Grandane A, Nocentini A, Domraceva I, Zalubovskis R, Supuran CT. Development of oxathiino[6,5-b]pyridine 2,2-dioxide derivatives as selective inhibitors of tumor-related carbonic anhydrases IX and XII. Eur J Med Chem. 2020;45:200.

 Google Scholar

Malebari AM, Ibrahim TS, Salem IM, et al. The anticancer activity for the bumetanide-based analogs via targeting the tumor-associated membrane-bound human carbonic anhydrase-IX enzyme. Pharmaceuticals-Base. 2020;13(9):e34.

 PubMed Web of Science ®Google Scholar

Hanson DJ, Nakamura S, Amachi R, et al. Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation. Oncotarget. 2015;6(32):33568–33586. doi:10.18632/oncotarget.5598

 PubMedGoogle Scholar

Beloueche-Babari M, Wantuch S, Galobart TC, et al. MCT1 inhibitor AZD3965 increases mitochondrial metabolism, facilitating combination therapy and noninvasive magnetic resonance spectroscopy. Cancer Res. 2017;77(21):5913–5924. doi:10.1158/0008-5472.CAN-16-2686

 PubMed Web of Science ®Google Scholar

Guan X, Rodriguez-Cruz V, Morris ME. Cellular uptake of MCT1 inhibitors AR-C155858 and AZD3965 and their effects on MCT-mediated transport of l-lactate in murine 4T1 breast tumor cancer cells. Aaps J. 2019;21(2). doi:10.1208/s12248-018-0279-5

 PubMed Web of Science ®Google Scholar

Liu YL, Ji XY, Tong WWL, et al. Engineering multifunctional RNAi nanomedicine to concurrently target cancer hallmarks for combinatorial therapy. Angewandte Chemie. 2018;57(6):1510–1513. doi:10.1002/anie.201710144

 Google Scholar

Puri S, Juvale K. Monocarboxylate transporter 1 and 4 inhibitors as potential therapeutics for treating solid tumours: a review with structure-activity relationship insights. Eur J Med Chem. 2020;45:199.

 Google Scholar

Renner K, Bruss C, Schnell A, et al. Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy. Cell Rep. 2019;29(1):135. doi:10.1016/j.celrep.2019.08.068

 PubMed Web of Science ®Google Scholar

Sadeghzadeh M, Moldovan RP, Teodoro R, Brust P, Wenzel B. One-step radiosynthesis of the MCTs imaging agent F-18 FACH by aliphatic F-18-labelling of a methylsulfonate precursor containing an unprotected carboxylic acid group. Sci Rep-Uk. 2019;9:45.

 PubMed Web of Science ®Google Scholar

Yang XK, Wang DS, Dong W, Song ZS, Dou KF. Expression and modulation of Na+/H+ exchanger 1 gene in hepatocellular carcinoma: a potential therapeutic target. J Gastroenterol Hepatol. 2011;26(2):364–370. doi:10.1111/j.1440-1746.2010.06382.x

 PubMed Web of Science ®Google Scholar

Yang X, Wang D, Dong W, Song Z, Dou K. Suppression of Na+/H+ exchanger 1 by RNA interference or amiloride inhibits human hepatoma cell line SMMC-7721 cell invasion. Med Oncol. 2011;28(1):385–390. doi:10.1007/s12032-010-9447-x

 PubMed Web of Science ®Google Scholar

Yang X, Wang D, Dong W, Song Z, Dou K. Inhibition of Na(+)/H(+) exchanger 1 by 5-(N-ethyl-N-isopropyl) amiloride reduces hypoxia-induced hepatocellular carcinoma invasion and motility. Cancer Lett. 2010;295(2):198–204. doi:10.1016/j.canlet.2010.03.001

 PubMed Web of Science ®Google Scholar

Wang J, Xu H, Wang Q, et al. CIAPIN1 targets Na+/H+ exchanger 1 to mediate MDA-MB-231 cells’ metastasis through regulation of MMPs via ERK1/2 signaling pathway. Exp Cell Res. 2015;333(1):60–72. doi:10.1016/j.yexcr.2015.02.012

 PubMed Web of Science ®Google Scholar

Guan XD, Luo LX, Begum G, et al. Elevated Na/H exchanger 1 (SLC9A1) emerges as a marker for tumorigenesis and prognosis in gliomas. J Exp Clin Canc Res. 2018;37:456.

 Web of Science ®Google Scholar

Zhu W, Carney KE, Pigott VM, et al. Glioma-mediated microglial activation promotes glioma proliferation and migration: roles of Na+/H+ exchanger isoform 1. Carcinogenesis. 2016;37(9):839–851. doi:10.1093/carcin/bgw068

 PubMed Web of Science ®Google Scholar

Amith SR, Wilkinson JM, Fliegel L. KR-33028, a potent inhibitor of the Na+/H+ exchanger NHE1, suppresses metastatic potential of triple-negative breast cancer cells. Biochem Pharmacol. 2016;118:31–39. doi:10.1016/j.bcp.2016.08.010

 PubMed Web of Science ®Google Scholar

Rolver MG, Elingaard-Larsen LO, Andersen AP, Counillon L, Pedersen SF. Pyrazine ring-based Na+/H+ exchanger (NHE) inhibitors potently inhibit cancer cell growth in 3D culture, independent of NHE1. Sci Rep-Uk. 2020;10(1):e65.

 PubMed Web of Science ®Google Scholar

Marala RB, Brown JA, Kong JX, et al. Zoniporide: a potent and highly selective inhibitor of human Na+/H+ exchanger-1. Eur J Pharmacol. 2002;451(1):37–41. doi:10.1016/S0014-2999(02)02193-3

 PubMed Web of Science ®Google Scholar

Wu DM, Doods H, Stassen JM. Inhibition of human pulmonary artery smooth muscle cell proliferation and migration by sabiporide, a new specific NHE-1 inhibitor. J Cardiovasc Pharm. 2006;48(2):34–40. doi:10.1097/01.fjc.0000239691.69346.6a

 PubMed Web of Science ®Google Scholar

Wang D, Balkovetz DF, Warnock DG. Mutational analysis of transmembrane histidines in the amiloride-sensitive Na+/H+ exchanger. Am J Physiol. 1995;269(2 Pt 1):C392–402. doi:10.1152/ajpcell.1995.269.2.C392

 PubMed Web of Science ®Google Scholar

Kim MJ, Moon CH, Kim MY, et al. KR-32570, a novel Na+/H+ exchanger-1 inhibitor, attenuates hypoxia-induced cell death through inhibition of intracellular Ca2+ overload and mitochondrial death. pathway in H9c2 cells. Eur J Pharmacol. 2005;525(1–3):1–7. doi:10.1016/j.ejphar.2005.09.043

 PubMed Web of Science ®Google Scholar

Kawamoto T, Kimura H, Kusumoto K, et al. Potent and selective inhibition of the human Na+/H+ exchanger isoform NHE1 by a novel aminoguanidine derivative T-162559. Eur J Pharmacol. 2001;420(1):1–8. doi:10.1016/S0014-2999(01)00991-8

 PubMed Web of Science ®Google Scholar

Lorrain J, Briand V, Favennec E, et al. Pharmacological profile of SL 59.1227, a novel inhibitor of the sodium/hydrogen exchanger. Brit J Pharmacol. 2000;131(6):1188–1194. doi:10.1038/sj.bjp.0703671

 PubMed Web of Science ®Google Scholar

He BY, Deng CS, Zhang M, Zou DD, Xu M. Reduction of intracellular pH inhibits the expression of VEGF in K562 cells after targeted inhibition of the Na+/H+ exchanger. Leukemia Res. 2007;31(4):507–514. doi:10.1016/j.leukres.2006.06.015

 PubMed Web of Science ®Google Scholar

Andersen AP, Flinck M, Oernbo EK, Pedersen NB, Viuff BM, Pedersen SF. Roles of acid-extruding ion transporters in regulation of breast cancer cell growth in a 3-dimensional microenvironment. Mol Cancer. 2016;15. doi:10.1186/s12943-016-0500-z

 PubMed Web of Science ®Google Scholar

Lee SP, Chao SC, Huang SF, Chen YL, Tsai YT, Loh SH. Expressional and functional characterization of intracellular ph regulators and effects of ethanol in human oral epidermoid carcinoma cells. Cell Physiol Biochem. 2018;47(5):2056. doi:10.1159/000491473

 PubMedGoogle Scholar

Giambelluca MS, Ciancio MC, Orlowski A, Gende OA, Pouliot M, Aiello EA. Characterization of the Na+/HCO3−cotransport in human neutrophils. Cell Physiol Biochem. 2014;33(4):982–990. doi:10.1159/000358669

 Google Scholar

Orlowski A, Vargas LA, Aiello EA, Alvarez BV. Elevated carbon dioxide upregulates NBCn1 Na+/HCO3− cotransporter in human embryonic kidney cells. Am J Physiol-Renal. 2013;305(12):F1765–F1774. doi:10.1152/ajprenal.00096.2013

 Google Scholar

Nordstrom T, Andersson LC, Akerman KEO. Regulation of intracellular pH by electrogenic Na+/HCO3−co-transporters in embryonic neural stem cell-derived radial glia-like cells. Bba-Biomembranes. 2019;1861(6):1037–1048. doi:10.1016/j.bbamem.2019.03.007

 Google Scholar