Assessing the Potential of Valproic Acid as an Adjuvant Agent among Various Histological Subtypes of Thyroid Cancer: A Systematic Review
Abstract
Background: Valproic acid (VPA) has gained attention as an anticonvulsant drug with potential anti-cancer effects, including in thyroid cancer. It hampers the viability of cancer cells by blocking their cell cycle progression, specifically in the G1 or sub-G1 phases. However, the clinical role of VPA as an adjuvant agent, in addition to the thyroid cancer primary treatment, remains an area of investigation.
Methods: We conducted a comprehensive systematic literature review from the first publication available to July 2021. We comprised clinical trials and preclinical investigations that explored VPA’s underlying mechanisms and treatment strategies in thyroid cancer.
Results: Fifteen eligible studies were included. Thirteen preclinical studies revealed that VPA significantly enhances therapeutic responses across various histological subtypes of thyroid cancer cells. Regarding clinical implications, recent clinical studies indicated no significant effect on tumor response or overall survival.
Conclusions: Our findings highlight the key role of VPA as an alternative therapeutic strategy for thyroid cancer, considering its favorable impact on various histological subtypes. Further welldesigned studies in clinical settings are required to identify the knowledge gap regarding its use in other multimodal treatments such as chemotherapy, surgery, and radiotherapy.
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DOI: 10.33371/ijoc.v18i4.1169
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References
Mattiuzzi C, Lippi G. Current Cancer Epidemiology. J Epidemiol Glob Health. 2019 Dec;9(4):217-22.
Montagnana M, Lippi G. Cancer diagnostics: current concepts and future perspectives. Ann Transl Med. 2017 Jul;5(13):268.
Khodamoradi F, Ghoncheh M, Mehri A, Hassanipour S, Salehiniya H. Incidence, Mortality, and risk factors of thyroid cancer in the world: a review. World Cancer Res J. 2018;5(2):9.
Prete A, Borges de Souza P, Censi S, Muzza M, Nucci N, Sponziello M. Update on Fundamental Mechanisms of Thyroid Cancer. Front Endocrinol (Lausanne). 2020;11:102.
Deng Y, Li H, Wang M, Li N, Tian T, Wu Y, et al. Global Burden of Thyroid Cancer From 1990 to 2017. JAMA Netw Open. 2020 Jun;3(6):e208759.
Chmielik E, Rusinek D, Oczko-Wojciechowska M, Jarzab M, Krajewska J, Czarniecka A, Jarzab B. Heterogeneity of Thyroid Cancer. Pathobiology. 2018;85(1-2):117-29.
Surveillance, Epidemiology, and End Results Program (SEER). Cancer Statistics Review, 1975–2018 [Internet]. National Cancer Institute; 2021. Available from: http://seer.cancer.gov/csr/1975_2018.
LiVolsi VA, Mazzaferri EL, Schneider AB, et al. Papillary carcinoma; in Delelils RA, Lloyd RV, Heitz PU, Eng C, editors. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Endocrine Organs. Lyon: International Agency for Research on Cancer; 2004. p. 57-66.
Kitahara CM, Schneider AB. Epidemiology of Thyroid Cancer. Cancer Epidemiol Biomarkers Prev. 2022 Jul;31(7):1284-97.
Brodie SA, Brandes JC. Could valproic acid be an effective anticancer agent? The evidence so far. Expert Rev Anticancer Ther. 2014 Oct;14[10]:1097-100.
Wawruszak A, Halasa M, Okon E, Kukula-Koch W, Stepulak A. Valproic Acid and Breast Cancer: State of the Art in 2021. Cancers [Basel]. 2021;13[14]:3409.
Tsai HC, Wei KC, Chen PY, Huang CY, Chen KT, Lin YJ, et al. Valproic Acid Enhanced Temozolomide-Induced Anticancer Activity in Human Glioma Through the p53-PUMA Apoptosis Pathway. Front Oncol. 2021;11:713298.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration. PLoS Med. 2009 Jul;6(7):e1000100.
Sterne JAC, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919.
Avram AM, Zukotynski K, Nadel HR, Giovanella L. Management of Differentiated Thyroid Cancer: The Standard of Care. J Nucl Med. 2022 Feb;63[2]:189-95.
Lorusso L, Cappagli V, Valerio L, Giani C, Viola D, Puleo L, e al. Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities. Int J Mol Sci. 2021 Mar 18;22(6):3117.
Sun YQ, Sun D, Zhang X, Zhang YQ, Lin YS. Radioiodine adjuvant therapy in differentiated thyroid cancer: An update and reconsideration. Front Endocrinol [Lausanne]. 2022 Nov 30;13:994288.
Clement SC, Peeters RP, Ronckers CM, et al. Intermediate and long-term adverse effects of radioiodine therapy for differentiated thyroid carcinoma: a systematic review. Cancer Treat Rev. 2015;41:925-34.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;371:m4729.
Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011 Apr;64(4):383-94.
Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE's risk of bias tool for animal studies. BMC Med Res Methodol. 2014 Mar 26;14:43.
Higgins JP, Altman D, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomized trials. BMJ. 2011;343:d5928.
Shen WT, Wong TS, Chung WY, Wong MG, Kebebew E, Duh QY, Clark OH. Valproic acid inhibits growth, induces apoptosis, and modulates apoptosis-regulatory and differentiation gene expression in human thyroid cancer cells. Surgery. 2005 Dec;138(6):979-84; discussion 984-5.
Fortunati N, Catalano MG, Arena K, Brignardello E, Piovesan A, Boccuzzi G. Valproic acid induces the expression of the Na+/I- symporter and iodine uptake in poorly differentiated thyroid cancer cells. J Clin Endocrinol Metab. 2004 Feb;89(2):1006-9.
Catalano MG, Fortunati N, Pugliese M, Costantino L, Poli R, Bosco O, Boccuzzi G. Valproic acid induces apoptosis and cell cycle arrest in poorly differentiated thyroid cancer cells. J Clin Endocrinol Metab. 2005 Mar;90(3):1383-9.
Cha HY, Lee BS, Kang S, Shin YS, Chang JW, Sung ES, et al. Valproic acid sensitizes TRAIL-resistant anaplastic thyroid carcinoma cells to apoptotic cell death. Ann Surg Oncol. 2013 Dec;20 Suppl 3: 716-24.
Fu YT, Zheng HB, Zhou L, Zhang DQ, Liu XL, Sun H. Valproic acid, targets papillary thyroid cancer through inhibition of c-Met signalling pathway. Am J Transl Res. 2017 Jun 15;9[6]:3138-3147.
Cha HY, Lee BS, Chang JW, Park JK, Han JH, Kim YS, et al. Downregulation of Nrf2 by the combination of TRAIL and Valproic acid induces apoptotic cell death of TRAIL-resistant papillary thyroid cancer cells via suppression of Bcl-xL. Cancer Lett. 2016 Mar 1;372(1):65-74.
Catalano MG, Poli R, Pugliese M, Fortunati N, Boccuzzi G. Valproic acid enhances tubulin acetylation and apoptotic activity of paclitaxel on anaplastic thyroid cancer cell lines. Endocr Relat Cancer. 2007 Sep;14(3):839-45.
Haghpanah V, Malehmir M, Larijani B, Ahmadian S, Alimoghaddam K, Heshmat R, et al. The Beneficial Effects of Valproic Acid in Thyroid Cancer Are Mediated through Promoting Redifferentiation and Reducing Stemness Level: An In Vitro Study. J Thyroid Res. 2014.
Gunel NS, Birden N, Kurt CC, Bagca BG, Shademan B, Sogutlu F, et al. Effect of valproic acid on miRNAs affecting histone deacetylase in a model of anaplastic thyroid cancer. Mol Biol Rep. 2021 Aug;48(8):6085-6091.
Catalano MG, Pugliese M, Poli R, Bosco O, Bertieri R, Fortunati N, Boccuzzi G. Effects of the histone deacetylase inhibitor valproic acid on the sensitivity of anaplastic thyroid cancer cell lines to imatinib. Oncol Rep. 2009 Feb;21(2):515-21.
Kim TH, Yoo YH, Kang DY, Suh H, Park MK, Park KJ, Kim SH. Efficacy on anaplastic thyroid carcinoma of valproic acid alone or in combination with doxorubicin, a synthetic chenodeoxycholic acid derivative, or lactacystin. Int J Oncol. 2009 May;34(5):1353-62.
Greenblatt DY, Cayo MA, Adler JT, Ning L, Haymart MR, Kunnimalaiyaan M, Chen H. Valproic acid activates Notch1 signalling and induces apoptosis in medullary thyroid cancer cells. Ann Surg. 2008 Jun;247[6]:1036-40.
Adler JT, Hottinger DG, Kunnimalaiyaan M, Chen H. Inhibition of growth in medullary thyroid cancer cells with histone deacetylase inhibitors and lithium chloride. J Surg Res. 2010 Apr;159(2):640-4.
Nilubol N, Merkel R, Yang L, Patel D, Reynolds JC, Sadowski SM, et al. A phase II trial of valproic acid in patients with advanced, radioiodine-resistant thyroid cancers of follicular cell origin. Clin Endocrinol (Oxf). 2017 Jan;86(1):128-133.
Catalano MG, Pugliese M, Gallo M, Brignardello E, Milla P, Orlandi F, e al. Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial. Int J Endocrinol. 2016.
Bãrbuş E, Peştean C, Larg MI, Piciu D. Quality of life in thyroid cancer patients: a literature review. Clujul Med. 2017;90[2]:147-153.
Nickel B, Tan T, Cvejic E, Baade P, McLeod DSA, Pandeya N, et al. Health-Related Quality of Life After Diagnosis and Treatment of Differentiated Thyroid Cancer and Association with Type of Surgical Treatment. JAMA Otolaryngol Head Neck Surg. 2019 Mar 1;145(3):231-238.
Li J, Xue LB, Gong XY, Yang YF, Zhang BY, Jin J, et al. Risk Factors of Deterioration in Quality of Life Scores in Thyroid Cancer Patients After Thyroidectomy. Cancer Manag Res. 2019 Dec 19;11: 10593-10598.
Sanaei M, Kavoosi F. Histone Deacetylases and Histone Deacetylase Inhibitors: Molecular Mechanisms of Action in Various Cancers. Adv Biomed Res. 2019 Oct 31;8:63.
Tassara M, Döhner K, Brossart P, Held G, Götze K, Horst HA, et al. Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients. Blood. 2014 Jun 26;123(26):4027-36.
Fushida S, Kinoshita J, Kaji M, Oyama K, Hirono Y, Tsukada T, et al. Paclitaxel plus valproic acid versus paclitaxel alone as second- or third-line therapy for advanced gastric cancer: a randomized Phase II trial. Drug Des Devel Ther. 2016 Jul 25;10: 2353-8.
Iwahashi S, Utsunomiya T, Imura S, Morine Y, Ikemoto T, Arakawa Y, et al. Effects of valproic acid in combination with S-1 on advanced pancreatobiliary tract cancers: clinical study phases I/II. Anticancer Res. 2014 Sep;34(9):5187-91.
Liu YC, Su CW, Ko PS, Lee RC, Liu CJ, Huang YH, et al. A clinical trial with valproic acid and hydralazine in combination with gemcitabine and cisplatin followed by doxorubicin and dacarbazine for advanced hepatocellular carcinoma. Asia Pac J Clin Oncol. 2022 Feb;18(1]):19-27.
Mohammed TA, Holen KD, Jaskula-Sztul R, Mulkerin D, Lubner SJ, Schelman WR, e al. A pilot phase II study of valproic acid for treatment of low-grade neuroendocrine carcinoma. Oncologist. 2011;16(6):835-43.
Nelson BE, Tsimberidou AM, Fu X, Fu S, Subbiah V, Sood AK, et al. A Phase I Trial of Bevacizumab and Temsirolimus in Combination with Valproic Acid in Advanced Solid Tumors. Oncologist. 2023 Jun 13: 158.
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