Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

Open Access 01-12-2021 | Thyroid Cancer | Research

Vitamin C sensitizes BRAFV600E thyroid cancer to PLX4032 via inhibiting the feedback activation of MAPK/ERK signal by PLX4032

Authors: Xi Su, Peng Li, Bin Han, Hao Jia, Qingzhuang Liang, Haichao Wang, Mengwei Gu, Jiaxuan Cai, Shaolei Li, Yaqi Zhou, Xin Yi, Wei Wei

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Login to get access

Abstract

Background

BRAFV600E mutation is the most common mutation in thyroid cancer. It strongly activates MAPK/ERK pathway and indicates an invasive subtype of thyroid cancer. PLX4032 is a selective oral inhibitor of the BRAFV600 kinase although with limited effect in treating this panel of thyroid cancer, due to the feedback activation of MAPK/ERK as well as PI3K/AKT pathways. It was investigated that Vitamin C plays a positive role in inhibiting these pathways in thyroid cancer. However, whether Vitamin C could enhance the antitumor effect of PLX4032 remains largely unclear.

Methods

The antitumor efficacy of combination therapy with PLX4032 and Vitamin C on BRAFMT thyroid cancer cell was assessed by the MTT assay, EdU assay and colony formation, Chou-Talalay way was employed to analyze the synergistic effect. Flow cytometry were employed to assess cells’ apoptosis and cell cycle arrest in response to combination therapy. Xenograft models were used to test its in vivo antitumor activity. Western blot and IHC were applied to investigate the mechanism underlying synergistic effect.

Results

PLX4032 or Vitamin C monotherapy was mildly effective in treating BRAFMT thyroid cancer cell and xenografts model. The combination therapy significantly inhibited cancer cell proliferation and tumor growth in nude mice, and induced cell apoptosis and cell cycle arrest compared to either monotherapy. PLX4032 monotherapy induced feedback activation of MAPK/ERK as well as PI3K/AKT pathway; while combination therapy significantly relieved this feedback.

Conclusion

Vitamin C promotes the antitumor effect of PLX4032 in BRAFMT thyroid cancer cell and xenografts model via relieving the feedback activation of MAPK/ERK as well as PI3K/AKT pathway. PLX4032/Vitamin C combination may be a potential therapeutic approach to treat BRAFMT thyroid cancer.
Appendix
Available only for authorised users
Literature
1.
Kitahara CM, Sosa JA. The changing incidence of thyroid cancer. Nat Rev Endocrinol. 2016;12(11):646–53.PubMedCrossRef
2.
3.
4.
Asa SL. The current histologic classification of thyroid Cancer. Endocrinol Metab Clin N Am. 2019;48(1):1–22.CrossRef
5.
Cancer Genome Atlas Research N. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159(3):676–90.CrossRef
6.
Xing M, Liu R, Liu X, Murugan AK, Zhu G, Zeiger MA, et al. BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol. 2014;32(25):2718–26.PubMedPubMedCentralCrossRef
7.
Guan H, Matonis D, Toraldo G, Lee SL. Clinical Significance of Thyroid-Stimulating Hormone Receptor Gene Mutations and/or Sodium-Iodine Symporter Gene Overexpression in Indeterminate Thyroid Fine Needle Biopsies. Front Endocrinol (Lausanne). 2018;9:566.PubMedCentralCrossRef
8.
Yao Y, Chen X, Yang H, Chen W, Qian Y, Yan Z, et al. Hsa_circ_0058124 promotes papillary thyroid cancer tumorigenesis and invasiveness through the NOTCH3/GATAD2A axis. J Exp Clin Cancer Res. 2019;38(1):318.PubMedPubMedCentralCrossRef
9.
Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855–67.PubMedCrossRef
10.
Cantwell-Dorris ER, O'Leary JJ, Sheils OM. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther. 2011;10(3):385–94.PubMedCrossRef
11.
Garnett MJ, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell. 2004;6(4):313–9.PubMedCrossRef
12.
13.
Espinosa AV, Porchia L, Ringel MD. Targeting BRAF in thyroid cancer. Br J Cancer. 2007;96(1):16–20.PubMedCrossRef
14.
Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373(8):726–36.PubMedPubMedCentralCrossRef
15.
Montero-Conde C, Ruiz-Llorente S, Dominguez JM, Knauf JA, Viale A, Sherman EJ, et al. Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas. Cancer Discov. 2013;3(5):520–33.PubMedPubMedCentralCrossRef
16.
Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K, et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science. 2015;350(6266):1391–6.PubMedPubMedCentralCrossRef
17.
Lv H, Wang C, Fang T, Li T, Lv G, Han Q, et al. Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2. NPJ Precis Oncol. 2018;2(1):1.PubMedPubMedCentralCrossRef
18.
19.
Klimant E, Wright H, Rubin D, Seely D, Markman M. Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach. Curr Oncol. 2018;25(2):139–48.PubMedPubMedCentralCrossRef
20.
Fiorillo M, Toth F, Sotgia F, Lisanti MP. Doxycycline, azithromycin and vitamin C (DAV): a potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs). Aging (Albany NY). 2019;11(8):2202–16.CrossRef
21.
Ghavami G, Sardari S. Synergistic effect of vitamin C with Cisplatin for inhibiting proliferation of gastric Cancer cells. Iran Biomed J. 2020;24(2):119–27.PubMedCrossRef
22.
Yang G, Yan Y, Ma Y, Yang Y. Vitamin C at high concentrations induces cytotoxicity in malignant melanoma but promotes tumor growth at low concentrations. Mol Carcinog. 2017;56(8):1965–76.PubMedCrossRef
23.
Su X, Shen Z, Yang Q, Sui F, Pu J, Ma JJ, et al. Vitamin C kills thyroid cancer cells through ROS-dependent inhibition of MAPK/ERK and PI3K/AKT pathways via distinct mechanisms. Theranostics. 2019;9(15):4461–73.PubMedPubMedCentralCrossRef
24.
Welkos S, O'Brien A. Determination of median lethal and infectious doses in animal model systems. Methods Enzymol. 1994;235:29–39.PubMedCrossRef
25.
Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58(3):621–81.PubMedCrossRef
26.
Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul. 1984;22:27–55.CrossRef
27.
28.
29.
Menon SS, Guruvayoorappan C, Sakthivel KM, Rasmi RR. Ki-67 protein as a tumour proliferation marker. Clin Chim Acta. 2019;491:39–45.PubMedCrossRef
30.
Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab. 2003;88(11):5399–404.PubMedCrossRef
31.
Xing M. BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr Rev. 2007;28(7):742–62.PubMedCrossRef
32.
Dadu R, Shah K, Busaidy NL, Waguespack SG, Habra MA, Ying AK, et al. Efficacy and tolerability of vemurafenib in patients with BRAF(V600E) -positive papillary thyroid cancer: M.D. Anderson Cancer center off label experience. J Clin Endocrinol Metab. 2015;100(1):E77–81.PubMedCrossRef
33.
Falchook GS, Millward M, Hong D, Naing A, Piha-Paul S, Waguespack SG, et al. BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. Thyroid. 2015;25(1):71–7.PubMedPubMedCentralCrossRef
34.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.PubMedPubMedCentralCrossRef
35.
Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483(7387):100–3.PubMedCrossRef
36.
Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2(3):227–35.PubMedPubMedCentralCrossRef
37.
Brose MS, Cabanillas ME, Cohen EE, Wirth LJ, Riehl T, Yue H, et al. Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(9):1272–82.PubMedPubMedCentralCrossRef
38.
Verrax J, Calderon PB. Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic Biol Med. 2009;47(1):32–40.PubMedCrossRef
39.
Du J, Martin SM, Levine M, Wagner BA, Buettner GR, Wang SH, et al. Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin Cancer Res. 2010;16(2):509–20.PubMedPubMedCentralCrossRef
40.
Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140(7):533–7.PubMedCrossRef
41.
Watabe T, Kaneda-Nakashima K, Liu Y, Shirakami Y, Ooe K, Toyoshima A, et al. Enhancement of (211)at uptake via the sodium iodide Symporter by the addition of ascorbic acid in targeted alpha-therapy of thyroid Cancer. J Nucl Med. 2019;60(9):1301–7.PubMedPubMedCentralCrossRef
42.
Lee SJ, Jeong JH, Lee IH, Lee J, Jung JH, Park HY, et al. Effect of high-dose vitamin C combined with anti-cancer treatment on breast Cancer cells. Anticancer Res. 2019;39(2):751–8.PubMedCrossRef
Metadata
Title
Vitamin C sensitizes BRAFV600E thyroid cancer to PLX4032 via inhibiting the feedback activation of MAPK/ERK signal by PLX4032
Authors
Xi Su
Peng Li
Bin Han
Hao Jia
Qingzhuang Liang
Haichao Wang
Mengwei Gu
Jiaxuan Cai
Shaolei Li
Yaqi Zhou
Xin Yi
Wei Wei
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-01831-y

Other articles of this Issue 1/2021

Journal of Experimental & Clinical Cancer Research 1/2021 Go to the issue

Correction

Correction to: Short hairpin RNA- mediated gene knockdown of FOXM1 inhibits the proliferation and metastasis of human colon cancer cells through reversal of epithelial-to-mesenchymal transformation

Research

Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1

Correction

Correction to: Cancer-associated fibroblasts promote the survival of irradiated nasopharyngeal carcinoma cells via the NF-κB pathway

Research

A receptor-antibody hybrid hampering MET-driven metastatic spread

Research

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Review

The emerging role of β-secretases in cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits