Current understanding of extrachromosomal circular DNA in cancer pathogenesis and therapeutic resistance

Abstract Extrachromosomal circular DNA was recently found to be particularly abundant in multiple human cancer cells, although its frequency varies among different tumor types. Elevated levels of extrachromosomal circular DNA have been considered an effective biomarker of cancer pathogenesis. Multiple reports have demonstrated that the amplification of oncogenes and therapeutic resistance genes located on extrachromosomal DNA is a frequent event that drives intratumoral genetic heterogeneity and provides a potential evolutionary advantage. This review highlights the current understanding of the extrachromosomal circular DNA present in the tissues and circulation of patients with advanced cancers and provides a detailed discussion of their substantial roles in tumor regulation. Confirming the presence of cancer-related extrachromosomal circular DNA would provide a putative testing strategy for the precision diagnosis and treatment of human malignancies in clinical practice.

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Cellular uptake and anticancer activity of carboxylated gallium corroles

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1517402113 ◽

2016 ◽

Vol 113 (16) ◽

pp. E2258-E2266 ◽

Cited By ~ 30

Author(s):

Melanie Pribisko ◽

Joshua Palmer ◽

Robert H. Grubbs ◽

Harry B. Gray ◽

John Termini ◽

...

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Tumor Imaging ◽

Human Cancer ◽

Melanoma Cells ◽

Intracellular Accumulation ◽

Human Cancer Cells ◽

High Cytotoxic Activity ◽

Tumor Types ◽

Confocal Fluorescence Imaging

We report derivatives of gallium(III) tris(pentafluorophenyl)corrole, 1 [Ga(tpfc)], with either sulfonic (2) or carboxylic acids (3, 4) as macrocyclic ring substituents: the aminocaproate derivative, 3 [Ga(ACtpfc)], demonstrated high cytotoxic activity against all NCI60 cell lines derived from nine tumor types and confirmed very high toxicity against melanoma cells, specifically the LOX IMVI and SK-MEL-28 cell lines. The toxicities of 1, 2, 3, and 4 [Ga(3-ctpfc)] toward prostate (DU-145), melanoma (SK-MEL-28), breast (MDA-MB-231), and ovarian (OVCAR-3) cancer cells revealed a dependence on the ring substituent: IC50 values ranged from 4.8 to >200 µM; and they correlated with the rates of uptake, extent of intracellular accumulation, and lipophilicity. Carboxylated corroles 3 and 4, which exhibited about 10-fold lower IC50 values (<20 µM) relative to previous analogs against all four cancer cell lines, displayed high efficacy (Emax = 0). Confocal fluorescence imaging revealed facile uptake of functionalized gallium corroles by all human cancer cells that followed the order: 4 >> 3 > 2 >> 1 (intracellular accumulation of gallium corroles was fastest in melanoma cells). We conclude that carboxylated gallium corroles are promising chemotherapeutics with the advantage that they also can be used for tumor imaging.

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Comparative Analysis of the Antitumor Activity of Cis- and Trans-Resveratrol in Human Cancer Cells with Different p53 Status

Molecules ◽

10.3390/molecules26185586 ◽

2021 ◽

Vol 26 (18) ◽

pp. 5586

Author(s):

Christian Leischner ◽

Markus Burkard ◽

Anja Michel ◽

Susanne Berchtold ◽

Heike Niessner ◽

...

Keyword(s):

Cell Lines ◽

Human Cancer ◽

Human Tumor ◽

Trans Form ◽

Trans Conformation ◽

Human Cancer Cells ◽

Tumor Entity ◽

Hct 116 ◽

Tumor Types ◽

Cis And Trans

Resveratrol, a natural plant phytoalexin, is produced in response to fungal infection or− UV irradiation. It exists as an isomeric pair with cis- and trans-conformation. Whereas multiple physiological effects of the trans-form, including a pronounced anti-tumoral activity, are nowadays elucidated, much less knowledge exists concerning the cis-isomer. In our work, we analyzed the antiproliferative and cytotoxic properties of cis-resveratrol in four different human tumor entities in direct comparison to trans-resveratrol. We used human cell lines as tumor models for hepatocellular carcinoma (HCC; HepG2, Hep3B), colon carcinoma (HCT-116, HCT-116/p53(−/−)), pancreatic carcinoma (Capan-2, MiaPaCa-2), and renal cell carcinoma (A498, SN12C). Increased cytotoxicity in all investigated tumor cells was observed for the trans-isomer. To verify possible effects of the tumor suppressor p53 on resveratrol-induced cell death, we used wild type and p53-deleted or -mutated cell lines for every tested tumor entity. Applying viability and cytotoxicity assays, we demonstrated a differential, dose-dependent sensitivity towards cis- or trans-resveratrol among the respective tumor types.

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Indirubin derivatives inhibit SFKs/Stat signaling associated with apoptosis in human cancer cells

Planta Medica ◽

10.1055/s-0028-1083855 ◽

2008 ◽

Vol 74 (09) ◽

Author(s):

S Nam ◽

R Buettner ◽

X Liu ◽

J Turkson ◽

D Kim ◽

...

Keyword(s):

Cancer Cells ◽

Human Cancer ◽

Human Cancer Cells ◽

Stat Signaling

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Structure-Reactivity Relationships on Substrates and Inhibitors of the Lysine Deacylase Sirtuin 2 from Schistosoma Mansoni (SmSirt2)

10.26434/chemrxiv.7957544 ◽

2019 ◽

Cited By ~ 1

Author(s):

Daria Monaldi ◽

Dante Rotili ◽

Julien Lancelot ◽

Martin Marek ◽

Nathalie Wössner ◽

...

Keyword(s):

Schistosoma Mansoni ◽

Human Cancer ◽

Egg Laying ◽

Human Cancer Cells ◽

Parasite Survival ◽

Survival And Reproduction ◽

Emergence Of Resistance ◽

First Time ◽

Parasitic Life Cycle

The only drug for treatment of Schistosomiasis is Praziquantel, and the possible emergence of resistance makes research on novel therapeutic agents necessary. Targeting of Schistosoma mansoni epigenetic enzymes, which regulate the parasitic life cycle, emerged as promising approach. Due to the strong effects of human Sirtuin inhibitors on parasite survival and reproduction, Schistosoma sirtuins were postulated as therapeutic targets. In vitro testing of synthetic substrates of S. mansoni Sirtuin 2 (SmSirt2) and kinetic experiments on a myristoylated peptide demonstrated lysine long chain deacylation as an intrinsic SmSirt2 activity for the first time. Focused in vitro screening of the GSK Kinetobox library and structure-activity relationships (SAR) of identified hits, led to the first SmSirt2 inhibitors with activity in the low micromolar range. Several SmSirt2 inhibitors showed potency against both larval schistosomes (viability) and adult worms (pairing, egg laying) in culture without general toxicity to human cancer cells.<br>

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