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mTOR Targeting Agents for the Treatment of Lymphoma and Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Andrea E. Wahner Hendrickson, Thomas E. Witzig, Scott H. Kaufmann
A number of preclinical observations provide the rationale for exploring mTOR inhibitors in acute myelogenous leukemia (AML). Recent work has demonstrated that as many as 80% of clinical AML samples exhibit constitutive PI3K/mTOR pathway activation (35,36). Importantly, AML blasts with pathway activation seem addicted to this signaling and exhibit increased susceptibility to mTOR inhibition in vitro (36,37). Additional experiments have demonstrated that sirolimus or everolimus causes dramatic enhancement of the cytotoxicity of the topoisomerase II poison etoposide (37) and the DNA methyltransferase inhibitor 5-azacytidine (38) in AML blasts in vitro.
Overview of Molecular Pathways in Melanoma
Published in Sanjiv S. Agarwala, Vernon K. Sondak, Melanoma, 2008
APAF-1, a proapoptotic factor downstream of p53, interacts with cyto-chrome c and procaspase-9 to induce apoptosis via the effector caspase pathway. Inactivation of APAF-1 through mutation and methylation has been shown in melanoma (109). Further, the proapoptotic activity of APAF-1, as well as chemo-sensitivity, was restored in melanoma cells by treatment with the DNA methyltransferase inhibitor, 5-aza-2′-deoxycitadine.
Vitamin C and Cancer
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Channing Paller, Tami Tamashiro, Thomas Luechtefeld, Amy Gravell, Mark Levine
An independent mechanism of the antitumor action of vitamin C involves an epigenetic DNA demethylation from activated ten-eleven translocation (TET) enzymes. Ascorbate increases TET enzyme activity, resulting in DNA demethylation and increased hydroxymethylation [75,76]. This can then cause a variety of actions: reexpression of tumor suppressor genes in cancer cells, inhibition of leukemogenesis, and expression of endogenous retrovirus transcripts that enhance immune signals induced by DNA methyltransferase inhibitor [54,77–80]. Ascorbate facilitates TET-mediated DNA demethylation by binding to the catalytic domain of TET enzymes [75,79], which reverses hypermethylation in tumors and activates tumor suppressor genes and mechanisms [79,81]. The TET2 gene is frequently mutated in hematopoietic malignancies and associated with DNA hypermethylation, heightened risk of myelodysplastic syndrome progression, and poor acute myeloid leukemia prognosis [82]. Vitamin C mimics restoration of TET2 in leukemic stem cells and enhances poly-ADP ribose polymerase inhibition in suppressing leukemia progression [78]. The ability of vitamin C to enhance TET function makes it a potential therapy for TET-associated malignancies, and future clinical trials should include high-dose vitamin C ancillary to standard chemotherapy/demethylating treatment, especially for TET2-deficient tumors [78]. It is currently unclear whether physiologic doses of vitamin C result in DNA demethylation, but it is hypothesized that vitamin C cofactor functions, such as DNA demethylation, would be similar or higher in pharmacologic doses [49]. Pharmacologic ascorbate also needs to be further investigated as a therapeutic treatment, in particular for malignancies with aberrant hypermethylation, including chronic myelomonocytic leukemia, myelodysplastic syndrome, acute myelogenous leukemia (TET2 aberration with either IDH1 or IDH2 aberration), clear-cell renal cell carcinoma, and succinate dehydrogenase mutated paraganglioma [83–90].
Perspectives on the future of urothelial carcinoma therapy: chemotherapy and beyond
Published in Expert Opinion on Pharmacotherapy, 2023
Alberto Bianchi, Markus von Deimling, Maximilian Pallauf, Takafumi Yanagisawa, Tatsushi Kawada, Hadi Mostafaei, Fahad Quhal, Ekaterina Laukhtina, Pawel Rajwa, Muhammad Majdoub, Reza Sari Motlagh, Benjamin Pradere, Pierre I. Karakiewicz, Maria Angela Cerruto, Alessandro Antonelli, Shahrokh F. Shariat
SPIRE, a phase Ib/IIa trial, evaluated the safety of the DNA methyltransferase inhibitor guadecitabine (SGI-110) in combination with GC (ISRCTN16332228). Results showed that adding guadecitabine to GC is tolerable, despite some additional myelosuppression. However, further investigation to assess its efficacy is warranted [114]. Fluorocyclopentenyl cytosine (RX- 3117), is another novel agent that is activated exclusively in the TME and acts by inhibiting DNA methyltransferase 1 and damaging DNA directly. Preliminary results from an ongoing phase IIa study, involving it as monotherapy for aUC (NCT02030067), suggest that RX-3117 is well-tolerated and capable of inducing partial response and tumor shrinkage in aUC patients [115]. Results from a phase Ib study with vorinostat, an HDACi, and pembrolizumab in metastatic urothelial, renal, and prostate carcinoma patients (NCT02619253) suggest that the combination regimen is relatively well tolerated and may be active in a subset of immune checkpoint resistant UC patients [116].
Breast cancer glycan biomarkers: their link to tumour cell metabolism and their perspectives in clinical practice
Published in Expert Review of Proteomics, 2021
Tomas Bertok, Veronika Pinkova Gajdosova, Aniko Bertokova, Natalia Svecova, Peter Kasak, Jan Tkac
An important area for future glycomic research may also include identifying a link between epigenetics and glycosylation in cancer. The DNA-methyltransferase inhibitor 5-AZA-dC (FDA approved) was shown not only to be potentially harmful for patients suffering from a chemo-sensitive cancer (ovarian and TNBCa), but also to be associated with aberrant glycosylation. Greville et al. proposed paying attention especially to ST3GAL4 and MGAT5 (affected by GATA2 and GATA3 transcription factors), responsible for sialylation and branching, respectively [98]. Moreover, the overexpression of MGAT5, responsible for increased branching of N-glycans, was shown to be associated with mis-/relocation of E-cadherin from the cell membrane to cytoplasm, causing a reduction in cell-cell adhesion and acquiring an invasive cell phenotype [99].
Epigenetic changes involved in hydroquinone-induced mutations
Published in Toxin Reviews, 2021
Minjuan Zeng, Shaopeng Chen, Ke Zhang, Hairong Liang, Jie Bao, Yuting Chen, Shiheng Zhu, Wei Jiang, Hui Yang, Yixian Wei, Lihao Guo, Huanwen Tang
The specific genes involved in hemin-induced erythroid differentiation in K562 cells include globin genes (α-, β-,and γ-globins), erythroid porphobilinogen deaminase (PBGD), and erythroid-specific transcription factors (GATA-1 and NF-E2). Li et al. (2013) showed that α-globin, β-globin, PBGD, and GATA-1 were hypermethylated in HQ-induced K562 cells, resulting in inhibition of hemin-induced erythroid differentiation. However, treatment with the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5-aza-CdR), prevented this process. In addition, Tang et al. (2016) found that hemin-induced hemoglobin synthesis, which was accompanied by elevated methylation, decreased in a concentration- and time-dependent manner in K562 cells after long-term exposure to benzene metabolites. These results indicate that DNA hypermethylation played a role in inhibiting hemin-induced erythroid differentiation or potential further malignancies of K562 cells by downregulating the transcription of several erythroid-related genes as well as the myeloid-specific gene, HOTAIRM1.