3 research outputs found
Dimers of Melampomagnolide B Exhibit Potent Anticancer Activity against Hematological and Solid Tumor Cells
Novel
carbamate (<b>7a</b>–<b>7h</b>) and carbonate
(<b>7i</b>, <b>7j</b>, and <b>8</b>) dimers of melampomagnolide
B have been synthesized by reaction of the melampomagnolide-B-triazole
carbamate synthon <b>6</b> with various terminal diamino- and
dihydroxyalkanes. Dimeric carbamate products <b>7b</b>,<b> 7c</b>, and <b>7f</b> exhibited potent growth inhibition
(GI<sub>50</sub> = 0.16–0.99 μM) against the majority
of cell lines in the NCI panel of 60 human hematological and solid
tumor cell lines. Compound <b>7f</b> and <b>8</b> exhibited
anticancer activity that was 300-fold and 1 × 10<sup>6</sup>-fold
more cytotoxic than DMAPT, respectively, at a concentration of 10
μM against rat 9L-SF gliosarcoma cells. Compounds <b>7a</b>–<b>7j</b> and <b>8</b> were also screened against
M9-ENL1 and acute myelogenous leukemia (AML) primary cell lines and
exhibited 2- to 10-fold more potent antileukemic activity against
M9-ENL1 cells (EC<sub>50</sub> = 0.57–2.90 μM) when compared
to parthenolide (EC<sub>50</sub> = 6.0) and showed potent antileukemic
activity against five primary AML cell lines (EC<sub>50</sub> = 0.76–7.3
μM)
A Small-Molecule Inhibitor of Human DNA Polymerase η Potentiates the Effects of Cisplatin in Tumor Cells
Translesion DNA synthesis
(TLS) performed by human DNA polymerase
eta (hpol η) allows tolerance of damage from <i>cis</i>-diammineÂdichloroplatinumÂ(II) (CDDP or cisplatin). We have
developed hpol η inhibitors derived from N-aryl-substituted
indole barbituric acid (IBA), indole thiobarbituric acid (ITBA), and
indole quinuclidine scaffolds and identified 5-((5-chloro-1-(naphthalen-2-ylmethyl)-1<i>H</i>-indol-3-yl)Âmethylene)-2-thioxodihydropyrimidine-4,6Â(1<i>H</i>,5<i>H</i>)-dione (PNR-7-02), an ITBA derivative
that inhibited hpol η activity with an IC<sub>50</sub> value
of 8 μM and exhibited 5–10-fold specificity for hpol
η over replicative pols. We conclude from kinetic analyses,
chemical footprinting assays, and molecular docking that PNR-7-02
binds to a site on the little finger domain and interferes with the
proper orientation of template DNA to inhibit hpol η. A synergistic
increase in CDDP toxicity was observed in hpol η-proficient
cells co-treated with PNR-7-02 (combination index values = 0.4–0.6).
Increased γH2AX formation accompanied treatment of hpol η-proficient
cells with CDDP and PNR-7-02. Importantly, PNR-7-02 did not impact
the effect of CDDP on cell viability or γH2AX in hpol η-deficient
cells. In summary, we observed hpol η-dependent effects on DNA
damage/replication stress and sensitivity to CDDP in cells treated
with PNR-7-02. The ability to employ a small-molecule inhibitor of
hpol η to improve the cytotoxic effect of CDDP may aid in the
development of more effective chemotherapeutic strategies
DataSheet1_Parthenolide induces rapid thiol oxidation that leads to ferroptosis in hepatocellular carcinoma cells.PDF
Hepatocellular carcinoma (HCC) is both a devastating and common disease. Every year in the United States, about 24,500 men and 10,000 women are diagnosed with HCC, and more than half of those diagnosed patients die from this disease. Thus far, conventional therapeutics have not been successful for patients with HCC due to various underlying comorbidities. Poor survival rate and high incidence of recurrence after therapy indicate that the differences between the redox environments of normal surrounding liver and HCC are valuable targets to improve treatment efficacy. Parthenolide (PTL) is a naturally found therapeutic with anti-cancer and anti-inflammatory properties. PTL can alter HCC’s antioxidant environment through thiol modifications leaving tumor cells sensitive to elevated reactive oxygen species (ROS). Investigating the link between altered thiol mechanism and increased sensitivity to iron-mediated lipid peroxidation will allow for improved treatment of HCC. HepG2 (human) and McARH7777 (rat) HCC cells treated with PTL with increasing concentrations decrease cell viability and clonogenic efficiency in vitro. PTL increases glutathione (GSH) oxidation rescued by the addition of a GSH precursor, N-acetylcysteine (NAC). In addition, this elevation in thiol oxidation results in an overall increase in mitochondrial dysfunction. To elucidate if cell death is through lipid peroxidation, using a lipid peroxidation sensor indicated PTL increases lipid oxidation levels after 6 h. Additionally, western blotting reveals glutathione peroxidase 4 (GPx4) protein levels decrease after treatment with PTL suggesting cells are incapable of preventing lipid peroxidation after exposure to PTL. An elevation in lipid peroxidation will lead to a form of cell death known as ferroptosis. To further establish ferroptosis as a critical mechanism of death for HCC in vitro, the addition of ferrostatin-1 combined with PTL demonstrates a partial recovery in a colony survival assay. This study reveals that PTL can induce tumor cell death through elevations in intracellular oxidation, leaving cells sensitive to ferroptosis.</p