Novel approaches to therapeutics in pancreatic adenocarcinoma: vitamin C and tumor treatment fields

Laith Abushahin , Travis Jones , Jonathan Song , Terence M. Williams , Haseebah Shahzad , Anne Noonan

Journal of Cancer Metastasis and Treatment ›› 2021, Vol. 7 : 19

PDF
Journal of Cancer Metastasis and Treatment ›› 2021, Vol. 7:19 DOI: 10.20517/2394-4722.2021.02
review-article

Novel approaches to therapeutics in pancreatic adenocarcinoma: vitamin C and tumor treatment fields

Author information +
History +
PDF

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited therapeutic options. Despite extensive clinical research over the past several decades, meaningful improvements in care standards have been challenging to achieve. Research efforts are underway on several fronts, including cytotoxic chemotherapy combinations, immunotherapy, and targeted therapy. In this review, we chose to focus less on mainstream avenues of clinical research in PDAC and highlight some novel and innovative research efforts that are typically outside the spotlight of therapies. Examples of these novel approaches include pharmacologic vitamin C and electromagnetic fields. This review’s scope is to present the biological basis of the anti-cancer potential and the early clinical data, as well as the future landscape of these agents, including ongoing clinical trials in these therapeutic avenues.

Keywords

Pancreas cancer / vitamin C / ascorbate / tumor treatment fields / induced electromagnetic field / electromagnetic field therapy

Cite this article

Download citation ▾
Laith Abushahin, Travis Jones, Jonathan Song, Terence M. Williams, Haseebah Shahzad, Anne Noonan. Novel approaches to therapeutics in pancreatic adenocarcinoma: vitamin C and tumor treatment fields. Journal of Cancer Metastasis and Treatment, 2021, 7: 19 DOI:10.20517/2394-4722.2021.02

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Ferlay J,Soerjomataram I.Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods.Int J Cancer2019;144:1941-53

[2]

Siegel RL,Jemal A.Cancer statistics, 2020.CA Cancer J Clin2020;70:7-30

[3]

Wagner M,Lietz M,Friess H.Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma.Br J Surg2004;91:586-94

[4]

Conroy T,Hebbar M.FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer.N Engl J Med2018;379:2395-406

[5]

Neoptolemos JP,Ghaneh P.Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.Lancet2017;389:1011-24

[6]

Oettle H,Hochhaus A.Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial.J AM MED ASSOC2013;310:1473-81

[7]

Rahib L,Matrisian LM.Evaluation of pancreatic cancer clinical trials and benchmarks for clinically meaningful future trials: a systematic review.JAMA Oncol2016;2:1209-16

[8]

Li Y.New developments and novel therapeutic perspectives for vitamin C.J Nutr2007;137:2171-84

[9]

Padayatty SJ,Hewitt SM,Hoffer LJ.Intravenously administered vitamin C as cancer therapy: three cases.CAN MED ASSOC J2006;174:937-42 PMCID:PMC1405876

[10]

Corti A,Pompella A.Cellular pathways for transport and efflux of ascorbate and dehydroascorbate.Arch Biochem Biophys2010;500:107-15

[11]

Vera JC,Zhang RH,Golde DW.Human HL-60 myeloid leukemia cells transport dehydroascorbic acid via the glucose transporters and accumulate reduced ascorbic acid.Blood1994;84:1628-34

[12]

Padayatty SJ.Vitamin C: the known and the unknown and Goldilocks.Oral Dis2016;22:63-93 PMCID:PMC4959991

[13]

Ngo B,Cantley LC.Targeting cancer vulnerabilities with high-dose vitamin C.Nat Rev Cancer2019;19:271-82 PMCID:PMC6526932

[14]

Vera JC,Fischbarg J.Mammalian facilitative hexose transporters mediate the transport of dehydroascorbic acid.Nature1993;364:79-82

[15]

Wilson JX.The physiological role of dehydroascorbic acid.FEBS Lett2002;527:5-9

[16]

Cameron E.Ascorbic acid and the glycosaminoglycans. An orthomolecular approach to cancer and other diseases.Oncology1973;27:181-92

[17]

Cameron E.Ascorbic acid, cell proliferation, and cancer.Lancet1972;1:542

[18]

Cameron E.The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer.Chem Biol Interact1974;9:285-315

[19]

Cameron E,Jack T.The orthomolecular treatment of cancer. III. Reticulum cell sarcoma: double complete regression induced by high-dose ascorbic acid therapy.Chem Biol Interact1975;11:387-93

[20]

Cameron E.Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer.Proc Natl Acad Sci U S A1978;75:4538-42 PMCID:PMC336151

[21]

Creagan ET,O'Fallon JR.Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial.N Engl J Med1979;301:687-90

[22]

Moertel CG,Creagan ET,O'Connell MJ.High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison.N Engl J Med1985;312:137-41

[23]

Padayatty SJ.New insights into the physiology and pharmacology of vitamin C.CMAJ2001;164:353-5 PMCID:PMC80729

[24]

Chen Q,Sun AY.Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice.Proc Natl Acad Sci U S A2008;105:11105-9 PMCID:PMC2516281

[25]

Waddell N,Patch AM.Whole genomes redefine the mutational landscape of pancreatic cancer.Nature2015;518:495-501 PMCID:PMC4523082

[26]

Polireddy K,Reed G.High dose parenteral ascorbate inhibited pancreatic cancer growth and metastasis: mechanisms and a phase I/IIa study.Sci Rep2017;7,17188 PMCID:PMC5719364

[27]

Verrax J.Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects.Free Radic Biol Med2009;47:32-40

[28]

Nauman G,Parkinson R,Paller CJ.Systematic review of intravenous ascorbate in cancer clinical trials.Antioxidants (Basel)2018;7:89 PMCID:PMC6071214

[29]

Chen Q,Krishna MC.Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues.Proc Natl Acad Sci U S A2005;102:13604-9 PMCID:PMC1224653

[30]

Buettner GR.The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate.Arch Biochem Biophys1993;300:535-43

[31]

Lane DJ.The active role of vitamin C in mammalian iron metabolism: much more than just enhanced iron absorption!.Free Radic Biol Med2014;75:69-83

[32]

Mastrangelo D,Castelli G,Testa U.Mechanisms of anti-cancer effects of ascorbate: cytotoxic activity and epigenetic modulation.Blood Cells Mol Dis2018;69:57-64

[33]

Klingelhoeffer C,Koospal M.Natural resistance to ascorbic acid induced oxidative stress is mainly mediated by catalase activity in human cancer cells and catalase-silencing sensitizes to oxidative stress.BMC Complement Altern Med2012;12:61 PMCID:PMC3404974

[34]

Doskey CM,Wagner BA.Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy.Redox Biol2016;10:274-84 PMCID:PMC5106370

[35]

Yun J,Lu C.Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH.Science2015;350:1391-6 PMCID:PMC4778961

[36]

Semenza GL.Pharmacologic targeting of hypoxia-inducible factors.Annu Rev Pharmacol Toxicol2019;59:379-403

[37]

Semenza GL.Targeting HIF-1 for cancer therapy.Nat Rev Cancer2003;3:721-32

[38]

Vissers MCM.Potential mechanisms of action for vitamin C in cancer: reviewing the evidence.Front Physiol2018;9:809 PMCID:PMC6037948

[39]

Ye HL,Zheng SY.Tumor-associated macrophages promote progression and the Warburg effect via CCL18/NF-kB/VCAM-1 pathway in pancreatic ductal adenocarcinoma.Cell Death Dis2018;9:453 PMCID:PMC5906621

[40]

Pfeifhofer-Obermair C,Petzer V,Nairz M.Iron in the tumor microenvironment-connecting the dots.Front Oncol2018;8:549 PMCID:PMC6275298

[41]

Jin X,Ma YL,Liu Z.Implications of HIF-1alpha in the tumorigenesis and progression of pancreatic cancer.Cancer Cell Int2020;20:273 PMCID:PMC7313137

[42]

Riordan HD,Jackson JA.Intravenous vitamin C as a chemotherapy agent: a report on clinical cases.P R Health Sci J2004;23:115-8

[43]

Hoffer LJ,Assouline S.Phase I clinical trial of i.v. ascorbic acid in advanced malignancy.Ann Oncol2008;19:1969-74

[44]

Monti DA,Bazzan AJ.Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.PLoS One2012;7:e29794 PMCID:PMC3260161

[45]

Welsh JL,van't Erve TJ.Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial.Cancer Chemother Pharmacol2013;71:765-75 PMCID:PMC3587047

[46]

Von Hoff DD,Arena FP.Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.N Engl J Med2013;369:1691-703 PMCID:PMC4631139

[47]

Levine M,Padayatty SJ.A new recommended dietary allowance of vitamin C for healthy young women.Proc Natl Acad Sci U S A2001;98:9842-6 PMCID:PMC55540

[48]

Pless M.Tumor treating fields: concept, evidence and future.Expert Opin Investig Drugs2011;20:1099-106

[49]

Goldberg SN,Mueller PR.Thermal ablation therapy for focal malignancy: a unified approach to underlying principles, techniques, and diagnostic imaging guidance.AJR Am J Roentgenol2000;174:323-31

[50]

Tofani S,Cintorino M.Static and ELF magnetic fields induce tumor growth inhibition and apoptosis.Bioelectromagnetics2001;22:419-28

[51]

Kirson ED,Schneiderman R.Disruption of cancer cell replication by alternating electric fields.Cancer Res2004;64:3288-95

[52]

Kirson ED,Tovarys F.Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors.Proc Natl Acad Sci U S A2007;104:10152-7 PMCID:PMC1886002

[53]

Giladi M,Voloshin T.Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells.Sci Rep2015;5:18046 PMCID:PMC4676010

[54]

Gera N,Holtzman TS,Wong ET.Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit.PLoS One2015;10:e0125269 PMCID:PMC4444126

[55]

Tuszynski JA,Friesen DE.An overview of sub-cellular mechanisms involved in the action of TTFields.Int J Environ Res Public Health2016;13:1128 PMCID:PMC5129338

[56]

Wenger C,Salvador R.A review on Tumor-Treating Fields (TTFields): clinical implications inferred from computational modeling.IEEE Rev Biomed Eng2018;11:195-207

[57]

Kessler AF,Gross F.Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition.Cell Death Discov2018;4:12 PMCID:PMC6125382

[58]

Voloshin T,Blatt R.Alternating electric fields (TTFields) in combination with paclitaxel are therapeutically effective against ovarian cancer cells in vitro and in vivo.Int J Cancer2016;139:2850-8 PMCID:PMC5095795

[59]

Shteingauz A,Voloshin T.AMPK-dependent autophagy upregulation serves as a survival mechanism in response to Tumor Treating Fields (TTFields).Cell Death Dis2018;9:1074 PMCID:PMC6195570

[60]

Karanam NK,Aroumougame A.Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: implications for cancer therapy.Transl Res2020;217:33-46

[61]

Berkelmann L,Meshksar S.Tumour-treating fields (TTFields): Investigations on the mechanism of action by electromagnetic exposure of cells in telophase/cytokinesis.Sci Rep2019;9:7362 PMCID:PMC6517379

[62]

Voloshin T,Davidi S.Tumor-treating fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy.Cancer Immunol Immunother2020;69:1191-204 PMCID:PMC7303058

[63]

Senovilla L,Martins I.An immunosurveillance mechanism controls cancer cell ploidy.Science2012;337:1678-84

[64]

Stingele S,Storchova Z.Activation of autophagy in cells with abnormal karyotype.Autophagy2013;9:246-8 PMCID:PMC3552891

[65]

Elliott MR,Trampont PC.Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance.Nature2009;461:282-6 PMCID:PMC2851546

[66]

Messmer D,Telusma G.High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization.J Immunol2004;173:307-13

[67]

Scaffidi P,Bianchi ME.Release of chromatin protein HMGB1 by necrotic cells triggers inflammation.Nature2002;418:191-5

[68]

Schneiderman R,Zeevi E.Tumor treating fields affect invasion properties and cell morphology of various cancer cells.Neuro-Oncology2018;20:iii282

[69]

Schneiderman RS,Zeevi E.Tumor treating fields (Ttfields) inhibit cancer cell migration and invasion by inducing reorganization of the actin cytoskeleton and formation of cell adhesions.Neuro-Oncology2018;20:vi30

[70]

Voloshin T,Volodin A.Tumor treating fields (TTFields) hinder cancer cell motility through regulation of microtubule and acting dynamics.Cancers (Basel)2020;12:3016 PMCID:PMC7603026

[71]

Garg AA,Moss SM.Electromagnetic fields alter the motility of metastatic breast cancer cells.Commun Biol2019;2:303 PMCID:PMC6687738

[72]

Giladi M,Porat Y.Mitotic disruption and reduced clonogenicity of pancreatic cancer cells in vitro and in vivo by tumor treating fields.Pancreatology2014;14:54-63

[73]

Rominiyi O,Clenton SJ,Al-Tamimi Y.Tumour treating fields therapy for glioblastoma: current advances and future directions.Br J Cancer2021;124:697-709 PMCID:PMC7884384

[74]

Stupp R,Kanner AA.NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality.Eur J Cancer2012;48:2192-202

[75]

Kesari S.EF-14 Trial InvestigatorsTumor-treating fields plus chemotherapy versus chemotherapy alone for glioblastoma at first recurrence: a post hoc analysis of the EF-14 trial.CNS Oncol2017;6:185-93 PMCID:PMC6009218

[76]

Rivera F,Gallego J,Lopez-Martine J.Tumor treating fields in combination with gemcitabine or gemcitabine plus nab-paclitaxel in pancreatic cancer: results of the PANOVA phase 2 study.Pancreatology2019;19:64-72

[77]

Weinberg U,Bomzon Z.PANOVA-3: a phase III study of tumor treating fields with nabpaclitaxel and gemcitabine for front-line treatment of locally advanced pancreatic adenocarcinoma (LAPC).JCO2019;37:TPS469

[78]

Renouf DJ,Kavan P.The canadian cancer trials group PA.7 trial: results of a randomized phase II study of gemcitabine (GEM) and nab-paclitaxel (Nab-P) vs GEM, nab-P, durvalumab (D) and tremelimumab (T) as first line therapy in metastatic pancreatic ductal adenocarcinoma (mPDAC).Annals of Oncology2020;31:S1195

[79]

Zheng L.Immune defects in pancreatic cancer.Ann Pancreat Cancer2018;1:33 PMCID:PMC6319882

AI Summary AI Mindmap
PDF

26

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/