Large pan-cancer cell screen coupled to (phospho-)proteomics underscores high-dose vitamin C as a potent anti-cancer agent

Author:

Vallés-Martí Andrea12ORCID,Böttger Franziska12,Yau Elysia12,Tejjani Khadija12,Meijs Loes12,Sharma Sugandhi12,Mumtaz Madiha12,Le Large Tessa Y. S.12,Erozenci Ayse12,Dekker Daniëlle34,Schelfhorst Tim12,Medema Jan Paul34,Bijnsdorp Irene V12,Knol Jaco C12,Piersma Sander R12,Pham Thang V.12,Giovannetti Elisa156,Jiménez Connie R12

Affiliation:

1. Amsterdam University Medical Center, VU University, Department of Medical Oncology

2. Cancer Center Amsterdam, OncoProteomics Laboratory

3. Cancer Center Amsterdam, Cancer Biology

4. Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory for Experimental Oncology and Radiobiology

5. Cancer Center Amsterdam, Pharmacology Laboratory

6. Cancer Pharmacology Lab, AIRC Start-Up unit, Fondazione Pisana per la Scienza

Abstract

Increasing preclinical and clinical evidence has positioned high-dose vitamin C as a promising anti-cancer treatment that merits more clinical attention. Multiple cytotoxicity mechanisms have been described, including pro-oxidant effects. To contribute to the preclinical understanding of the broad pan-cancer effects of high-dose vitamin C in a global manner, we determined the IC50 of a large panel of cancer cell lines (n=51) representing 7 solid tumour types and generated proteome data. The majority of cell lines were highly sensitive (IC50 range 0.036-10mM, mean 1.7 ± 0.4 mM), well below a clinically achievable dose. The proteome data (>5000 proteins per sample), showed that high sensitivity is associated with proliferation, as indicated by functional enrichment of cell cycle, RNA splicing and chromatin organization, while lower sensitivity is linked to extracellular vesicles, glycolysis, fatty acid metabolism and mitochondria. Moreover, (phospho-)proteome analysis of on-treatment vitamin C effects on four pancreatic ductal adenocarcinoma (PDAC) cells dosed at a range of IC50 values (Hs766 T, 2 mM; Capan-2, 0.6 mM; PANC-1, 0.14 mM and Suit-2, 0.1 mM) revealed, next to cell line specific effects, down-modulation of AKT-MTOR signalling and immune suppressive signalling, while IFN-α response was enhanced upon vitamin C. Altogether, our comprehensive pharmacological and (phospho-)proteome analysis is the first to assess cancer vulnerabilities and effects of vitamin C on a large cancer cell line panel and underscores the potential of high-dose vitamin C as an anti-cancer agent.

Publisher

eLife Sciences Publications, Ltd

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