Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia

Brabson, John P.; Leesang, Tiffany; Yap, Yoon Sing; Wang, Jingjing; Lam, Minh Quang; Fang, Byron; Dolgalev, Igor; Barbieri, Daniela A.; Strippoli, V.; Bañuelos, Carolina; Mohammad, Sofia; Lyon, Peter; Chaudhry, Sana; Donich, Dane; Swirski, Anna; Roberts, Evan R.; Diaz, Ivelisse; Karl, Daniel; Santos, Helena; Shiekhattar, Ramin; Neel, Benjamin G.; Nimer, Stephen D.; Verdún, Ramiro E.; Bilbao, Daniel; Figueroa, María E.; Cimmino, Luisa

doi:10.1016/j.celrep.2023.112027

Cited by 6 publications

(3 citation statements)

References 79 publications

(101 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The activities of these enzymes contribute to the suppression of oncogenes and the re-expression of tumor suppressor genes, resulting in post-translational and/or epigenetic anti-tumor effects in both hematological and solid tumors [36,79,80]. Indeed, a growing number of studies report the involvement of these enzymes in VC-induced tumor suppression across multiple cancer types, including leukemia, melanoma, and renal cell carcinoma [4,[79][80][81][82].…”

Section: Physiological and Anti-tumor Activities Of Vitamin Cmentioning

confidence: 99%

Role of Vitamin C in Targeting Cancer Stem Cells and Cellular Plasticity

Lee

2023

Cancers

View full text Add to dashboard Cite

Vitamin C (VC) is an essential nutrient that is vital for maintaining cellular physiology. Interestingly, it functions as either an antioxidant or a pro-oxidant, depending on the concentration used. At high-doses, VC selectively targets various cancer cell types through its pro-oxidant action, while at low-doses, VC enhances anti-tumor immunity by acting as an antioxidant. This versatility makes VC a promising anti-tumor agent for both standalone and combination therapies. Tumors consist of diverse cancer cell subtypes with distinct phenotypic and functional characteristics. In particular, cancer stem cells (CSCs), which are self-renewing multi-potent cells, are responsible for tumor recurrence, metastasis, chemoresistance, and heightened mortality. CSCs are often associated with the epithelial–mesenchymal transition (EMT), which confers increased motility and invasive capabilities that are characteristic of malignant and drug-resistant cells. Thus, eradicating CSC populations is crucial and has led to extensive efforts aimed at identifying medicines that can target them. Recent studies suggest that VC can selectively target CSCs via epigenetic and metabolic pathways in various cancers. Here, we highlight recent progress that has been made in understanding how VC effectively targets CSC evolution, providing a rationale for the use of VC either alone or in combination with other treatments to improve outcomes.

show abstract

Section: Physiological and Anti-tumor Activities Of Vitamin Cmentioning

confidence: 99%

Role of Vitamin C in Targeting Cancer Stem Cells and Cellular Plasticity

Lee

2023

Cancers

View full text Add to dashboard Cite

show abstract

“…Consistent with frequent TET inactivation in cancers, physiological vitamin C levels are markedly reduced in many cancer patients, compared with healthy individuals [32][33][34]. Many studies have reported that vitamin C increases 5hmC in cancer cell lines including leukemia, hepatocellular carcinoma, and colorectal cancer [35][36][37][38][39], demonstrating therapeutic efficacy, particularly in the treatment of hematological cancers [25,27]. Additionally, FDA-approved drugs like ivosidenib [40] and enasidenib [41] targeting IDH1 and IDH2, respectively, demonstrated clinical efficacy in IDH-mutated AML [42][43][44], glioma [45][46][47], and cholangiocarcinoma [48,49], either alone or in combination.…”

Section: Introductionmentioning

confidence: 97%

“…Notably, the restoration of TET enzyme expression or function inhibits cancer progression [18,[20][21][22][23][24][25][26][27]. The overexpression of TET1 inhibited colon cancer formation in mice by derepressing inhibitors of the WNT pathway such as DKK3 and DKK4 [22].…”

Section: Introductionmentioning

confidence: 99%

Development of Novel Epigenetic Anti-Cancer Therapy Targeting TET Proteins

Kim,

Jung,

Lee

et al. 2023

IJMS

View full text Add to dashboard Cite

Epigenetic dysregulation, particularly alterations in DNA methylation and hydroxymethylation, plays a pivotal role in cancer initiation and progression. Ten-eleven translocation (TET) proteins catalyze the successive oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized methylcytosines in DNA, thereby serving as central modulators of DNA methylation–demethylation dynamics. TET loss of function is causally related to neoplastic transformation across various cell types while its genetic or pharmacological activation exhibits anti-cancer effects, making TET proteins promising targets for epigenetic cancer therapy. Here, we developed a robust cell-based screening system to identify novel TET activators and evaluated their potential as anti-cancer agents. Using a carefully curated library of 4533 compounds provided by the National Cancer Institute, Bethesda, MD, USA, we identified mitoxantrone as a potent TET agonist. Through rigorous validation employing various assays, including immunohistochemistry and dot blot studies, we demonstrated that mitoxantrone significantly elevated 5hmC levels. Notably, this elevation manifested only in wild-type (WT) but not TET-deficient mouse embryonic fibroblasts, primary bone marrow-derived macrophages, and leukemia cell lines. Furthermore, mitoxantrone-induced cell death in leukemia cell lines occurred in a TET-dependent manner, indicating the critical role of TET proteins in mediating its anti-cancer effects. Our findings highlight mitoxantrone’s potential to induce tumor cell death via a novel mechanism involving the restoration of TET activity, paving the way for targeted epigenetic therapies in cancer treatment.

show abstract

Redox-active vitamin C suppresses human osteosarcoma growth by triggering intracellular ROS-iron–calcium signaling crosstalk and mitochondrial dysfunction

Vaishampayan,

Lee

2024

Redox Biology

View full text Add to dashboard Cite

Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia

Cited by 6 publications

References 79 publications

Role of Vitamin C in Targeting Cancer Stem Cells and Cellular Plasticity

Role of Vitamin C in Targeting Cancer Stem Cells and Cellular Plasticity

Development of Novel Epigenetic Anti-Cancer Therapy Targeting TET Proteins

Redox-active vitamin C suppresses human osteosarcoma growth by triggering intracellular ROS-iron–calcium signaling crosstalk and mitochondrial dysfunction

Contact Info

Product

Resources

About