Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6‑diazo‑5‑oxo‑L‑norleucine and orlistat in colon cancer

Cervantes‑Madrid,Diana; Dominguez‑Gomez,Guadalupe; Gonzalez‑Fierro,Aurora; Perez‑Cardenas,Enrique; Taja‑Chayeb,Lucia; Trejo-Becerril,Catalina; Duenas‑Gonzalez,Alfonso

doi:10.3892/ol.2017.5615

Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6‑diazo‑5‑oxo‑L‑norleucine and orlistat in colon cancer

Authors:
- Diana Cervantes‑Madrid
- Guadalupe Dominguez‑Gomez
- Aurora Gonzalez‑Fierro
- Enrique Perez‑Cardenas
- Lucia Taja‑Chayeb
- Catalina Trejo-Becerril
- Alfonso Duenas‑Gonzalez
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Affiliations: Division of Basic Research, National Cancer Institute, Mexico City 14080, Mexico, Unit of Biomedical Research on Cancer, Institute of Biomedical Investigations, National Autonomous University of Mexico/National Cancer Institute, Mexico City 14080, Mexico
Published online on: January 18, 2017 https://doi.org/10.3892/ol.2017.5615
Pages: 1905-1910

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Abstract

The aim of the present study was to investigate in vivo the feasibility and efficacy of the combination of lonidamine (LND), 6‑diazo‑5‑oxo‑L‑norleucine (DON) and orlistat to simultaneously target glycolysis, glutaminolysis and de novo synthesis of fatty acids, respectively. The doses of LND and DON used in humans were translated to mouse doses (77.7 mg/kg and 145.5 mg/kg, respectively) and orlistat was used at 240 mg/kg. Three schedules of LND, DON and orlistat at different doses were administered by intraperitoneal injection to BALB/c mice in a 21‑day cycle (schedule 1: LND, 0.5 mg/day; DON, 0.25 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 2: LND, 0.1 mg/day; DON, 0.5 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 3: LND, 0.5 mg/day; DON, 0.08 mg/day 1, 5 and 9; orlistat, 360 mg/kg/day) to assess tolerability. To determine the antitumor efficacy, a syngeneic tumor model in BALB/c mice was created using colon cancer CT26.WT cells, and a xenogeneic tumor model was created in nude mice using the human colon cancer SW480 cell line. Mice were treated with schedule 1. Animals were weighed, clinically inspected during the experiment and the tumor volume was measured at day 21. The 3 schedules assessed in the tolerability experiments were well tolerated, as mice maintained their weight and no evident clinical signs of toxicity were observed. Combination treatment with schedule 1 significantly decreased tumor growth in each mouse model. No evident signs of toxicity were observed and mice maintained their weight during treatment. The triple metabolic blockade of the malignant phenotype appears feasible and promising for cancer therapy.

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1	Chen JQ and Russo J: Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochim Biophys Acta. 1826:370–384. 2012.PubMed/NCBI
2	Moncada S, Higgs EA and Colombo SL: Fulfilling the metabolic requirements for cell proliferation. Biochem J. 446:1–7. 2012. View Article : Google Scholar : PubMed/NCBI
3	Menendez JA and Lupu R: Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 7:763–767. 2007. View Article : Google Scholar : PubMed/NCBI
4	Tan NL and Seyfried TN: Influence of serum and hypoxia on incorporation of [(14)C]-D-glucose or [(14)C]-L-glutamine into lipids and lactate in murine glioblastoma cells. Lipids. 50:1167–1184. 2015. View Article : Google Scholar : PubMed/NCBI
5	Cervantes-Madrid D, Romero Y and Dueñas-González A: Reviving lonidamine and 6-Diazo-5-oxo-L-norleucine to be used in combination for metabolic cancer therapy. Biomed Res Int. 2015:6904922015. View Article : Google Scholar : PubMed/NCBI
6	Lupu R and Menendez JA: Pharmacological inhibitors of fatty acid synthase (FASN)-catalyzed endogenous fatty acid biogenesis: A new family of anti-cancer agents? Curr Pharm Biotechnol. 7:483–493. 2006. View Article : Google Scholar : PubMed/NCBI
7	Kridel SJ, Axelrod F, Rozenkrantz N and Smith JW: Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 64:2070–2075. 2004. View Article : Google Scholar : PubMed/NCBI
8	Flavin R, Peluso S, Nguyen PL and Loda M: Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 6:551–562. 2010. View Article : Google Scholar : PubMed/NCBI
9	Cervantes-Madrid D and Dueñas-González A: Antitumor effects of a drug combination targeting glycolysis, glutaminolysis and de novo synthesis of fatty acids. Oncol Rep. 34:1533–1542. 2015.PubMed/NCBI
10	Reagan-Shaw S, Nihal M and Ahmad N: Dose translation from animal to human studies revisited. FASEB J. 22:659–661. 2008. View Article : Google Scholar : PubMed/NCBI
11	Elf SE and Chen J: Targeting glucose metabolism in patients with cancer. Cancer. 120:774–780. 2014. View Article : Google Scholar : PubMed/NCBI
12	Jin L, Alesi GN and Kang S: Glutaminolysis as a target for cancer therapy. Oncogene. 35:3619–3625. 2016. View Article : Google Scholar : PubMed/NCBI
13	Deepa PR, Vandhana S, Jayanthi U and Krishnakumar S: Therapeutic and toxicologic evaluation of anti-lipogenic agents in cancer cells compared with non-neoplastic cells. Basic Clin Pharmacol Toxicol. 110:494–503. 2012. View Article : Google Scholar : PubMed/NCBI
14	Ganapathy-Kanniappan S and Geschwind JF: Tumor glycolysis as a target for cancer therapy: Progress and prospects. Mol Cancer. 12:1522013. View Article : Google Scholar : PubMed/NCBI
15	Di Cosimo S, Ferretti G, Papaldo P, Carlini P, Fabi A and Cognetti F: Lonidamine: Efficacy and safety in clinical trials for the treatment of solid tumors. Drugs Today (Barc). 39:157–174. 2003. View Article : Google Scholar : PubMed/NCBI
16	Dwarakanath BS, Singh D, Banerji AK, Sarin R, Venkataramana NK, Jalali R, Vishwanath PN, Mohanti BK, Tripathi RP, Kalia VK and Jain V: Clinical studies for improving radiotherapy with 2-deoxy-D-glucose: Present status and future prospects. J Cancer Res Ther. 5:(Suppl 1). S21–S26. 2009. View Article : Google Scholar : PubMed/NCBI
17	Garon EB, Christofk HR, Hosmer W, Britten CD, Bahng A, Crabtree MJ, Hong CS, Kamranpour N, Pitts S, Kabbinavar F, et al: Dichloroacetate should be considered with platinum-based chemotherapy in hypoxic tumors rather than as a single agent in advanced non-small cell lung cancer. J Cancer Res Clin Oncol. 140:443–452. 2014. View Article : Google Scholar : PubMed/NCBI
18	Catane R, Von Hoff DD, Glaubiger DL and Muggia FM: Azaserine, DON, and azotomycin: Three diazo analogs of L-glutamine with clinical antitumor activity. Cancer Treat Rep. 63:1033–1038. 1979.PubMed/NCBI
19	Unger C, Mueller C, Bausch MP, Krzemieniecki K, Ochenduszko S, Wilk B, Jaeger E and Al-Batran S: A phase I schedule optimization study of pegylated glutaminase (PEG-PGA) plus 6-diazo-5-oxo-l-norleucine (DON) in patients (pts) with advanced solid tumors. J Clin Oncol. 29:(Suppl) abstr 3049. 2011.
20	Griffiths M, Keast D, Patrick G, Crawford M and Palmer TN: The role of glutamine and glucose analogues in metabolic inhibition of human myeloid leukaemia in vitro. Int J Biochem. 25:1749–1755. 1993. View Article : Google Scholar : PubMed/NCBI
21	Paulmurugan R, Bhethanabotla R, Mishra K, Devulapally R, Foygel K, Sekar TV, Ananta JS, Massoud TF and Joy A: Folate receptor targeted polymeric micellar nanocarriers for delivery of orlistat as a repurposed drug against triple negative breast cancer. Mol Cancer Ther. 15:221–231. 2016. View Article : Google Scholar : PubMed/NCBI
22	Zhi J, Mulligan TE and Hauptman JB: Long-term systemic exposure of orlistat, a lipase inhibitor, and its metabolites in obese patients. J Clin Pharmacol. 39:41–46. 1999. View Article : Google Scholar : PubMed/NCBI
23	De Cesare M, Pratesi G, Giusti A, Polizzi D and Zunino F: Stimulation of the apoptotic response as a basis for the therapeutic synergism of lonidamine and cisplatin in combination in human tumour xenografts. Br J Cancer. 77:434–439. 1998. View Article : Google Scholar : PubMed/NCBI
24	Nath K, Nelson DS, Heitjan DF, Leeper DB, Zhou R and Glickson JD: Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin. NMR Biomed. 28:281–290. 2015. View Article : Google Scholar : PubMed/NCBI
25	Ovejera AA, Houchens DP, Catane R, Sheridan MA and Muggia FM: Efficacy of 6-diazo-5-oxo-L-norleucine and N-(N-gamma-glutamyl-6-diazo-5-oxo-norleucinyl)-6-diazo-5- oxo-norleucine against experimental tumors in conventional and nude mice. Cancer Res. 39:3220–3224. 1979.PubMed/NCBI
26	Heiden MG Vander: Targeting cancer metabolism: A therapeutic window opens. Nat Rev Drug Discov. 10:671–684. 2011. View Article : Google Scholar : PubMed/NCBI
27	Guo L, Shestov AA, Worth AJ, Nath K, Nelson DS, Leeper DB, Glickson JD and Blair IA: Inhibition of mitochondrial complex II by the anti-cancer agent lonidamine. J Biol Chem. 291:42–57. 2016. View Article : Google Scholar : PubMed/NCBI
28	Assanhou AG, Li W, Zhang L, Xue L, Kong L, Sun H, Mo R and Zhang C: Reversal of multidrug resistance by co-delivery of paclitaxel and lonidamine using a TPGS and hyaluronic acid dual-functionalized liposome for cancer treatment. Biomaterials. 73:284–295. 2015. View Article : Google Scholar : PubMed/NCBI
29	Olsen RR, Mary-Sinclair MN, Yin Z and Freeman KW: Antagonizing Bcl-2 family members sensitizes neuroblastoma and Ewing's sarcoma to an inhibitor of glutamine metabolism. PLoS One. 10:e01169982015. View Article : Google Scholar : PubMed/NCBI