Inhibition of NF-κB and DNA double-strand break repair by DMAPT sensitizes non-small-cell lung cancers to X-rays

Estabrook, Neil C.; Chin-Sinex, Helen; Borgmann, Anthony J.; Dhaemers, Ryan; Shapiro, Rachel; Gilley, David; Huda, Nazmul; Crooks, Peter A.; Sweeney, Christopher J.; Mendonca, Marc S.

doi:10.1016/j.freeradbiomed.2011.09.029

Cited by 23 publications

(56 citation statements)

References 43 publications

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“…Cells in exponential growth phase were harvested and plated in T-75 and T-25 flasks (Corning) for stock propagation and experiments, respectively, by our standard methods [11,32,33]. The flasks were placed in a 37°C incubator with 5% CO 2 levels and 85% humidity (Forma Steri-Cult HEPA Class 100 CO 2 incubator, Thermo Scientific).…”

Section: Cell Culturementioning

confidence: 99%

“…A growth curve of cell counts versus time was generated for treated and nontreated samples at 24, 48, 72, and 96 h. The growth curves for A549 and H1299 cells with 0 and 50 mM DCA were graphically analyzed and the population doubling times determined by our standard methods [11,32,33]. To assess the effect of DCA on plating efficiency (PE), i.e., colony formation, adherent cells from the A549 and H1299 treatment flasks above were trypsinized, counted, and plated at appropriate numbers for colony formation assays by our standard methods [11,32,33].…”

Section: Plating Efficiency/colony Formation Assays and Population Domentioning

confidence: 99%

“…Stained colonies with at least 50 cells per colony were scored. PE was defined as the ratio of scored colonies to number of cells plated [11,32,33].…”

Section: Plating Efficiency/colony Formation Assays and Population Domentioning

confidence: 99%

“…The X-ray machine had a 0.5 mm of Cu filtration and the source to target distance was 33 cm, which resulted in a dose rate of 62.8 cGy/min. The specimens were allowed to recover for 24 h and the adherent cells were trypsinized, counted, and plated at appropriate numbers for colony formation assays by our standard methods [11,32,33]. The colonies were allowed to grow for 10 days before fixation with 70% ethanol followed by crystal violet staining (3%).…”

Section: Clonogenic Survival Assays and X-ray Survival Curve Construcmentioning

confidence: 99%

“…An alternative methodology for these NSCLC patients with large tumors is to combine targeted and untargeted chemotherapy drugs with radiation to increase the tumor-killing efficacy with a lower radiation dose, and thereby perhaps limit damage to normal Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/freeradbiomed tissue surrounding their NSCLC tumors [11][12][13]. However, a number of studies strongly suggest that targeting abnormal cancer cell metabolism such as aerobic glycolysis or Warburg metabolism with metabolic agents should be investigated as a potential therapeutic approach in combination with radiation or chemotherapy [14][15][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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Dichloroacetate alters Warburg metabolism, inhibits cell growth, and increases the X-ray sensitivity of human A549 and H1299 NSC lung cancer cells

Allen

Chin-Sinex

DeLuca

et al. 2015

Free Radical Biology and Medicine

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Section: Cell Culturementioning

confidence: 99%

Section: Plating Efficiency/colony Formation Assays and Population Domentioning

confidence: 99%

“…Stained colonies with at least 50 cells per colony were scored. PE was defined as the ratio of scored colonies to number of cells plated [11,32,33].…”

Section: Plating Efficiency/colony Formation Assays and Population Domentioning

confidence: 99%

Section: Clonogenic Survival Assays and X-ray Survival Curve Construcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Dichloroacetate alters Warburg metabolism, inhibits cell growth, and increases the X-ray sensitivity of human A549 and H1299 NSC lung cancer cells

Allen

Chin-Sinex

DeLuca

et al. 2015

Free Radical Biology and Medicine

Self Cite

View full text Add to dashboard Cite

Actinomycin‐D and dimethylamino‐parthenolide synergism in treating human pancreatic cancer cells

Lamture

Crooks

Borrelli

2018

Drug Development Research

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Pancreatic cancer is the third leading cause of death in the US with a poor 5-year survival rate of 8.5%. A novel anti-cancer drug, dimethylamino-parthenolide (DMAPT), is the water-soluble analog of the natural sesquiterpene lactone, parthenolide. The putative modes of action of DMAPT are inhibition of the NFκB pathway and depletion of glutathione levels; the latter causing cancer cells to be more susceptible to oxidative stress-induced cell death. Actinomycin-D is a polypeptide antibiotic that binds to DNA and inhibits RNA and protein synthesis by inhibiting RNA polymerase II. A phase 2 clinical trial indicated that Actinomycin-D could be a potent drug against pancreatic cancer; however, it was not a favored drug due to toxicity issues. New drug entities and methods of drug delivery, used alone or in combination, are needed to treat pancreatic cancer more effectively. Thus, it was postulated that combining DMAPT and Actinomycin-D would result in synergistic inhibition of Panc-1 pancreatic cancer cell growth because DMAPT's inhibition of NFκB would enhance induction of apoptosis by Actinomycin-D, via phosphorylation of c-Jun, by minimizing NFκB inhibition of c-Jun phosphorylation. Combining these two drugs induced a higher level of cell death than each drug alone. A fixed drug ratio of DMAPT: Actinomycin-D (1200:1) was used. Data from metabolic (MTT) and colony formation assays were analyzed for synergism with CompuSyn software, which utilizes the Chou-Talalay equation. The analyses indicated synergism and moderate synergism at combination concentrations of DMAPT/Actinomycin-D of 12/0.01 and 18/0.015 µM, respectively.

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Dimethylaminoparthenolide reduces the incidence of dysplasia and ameliorates a wasting syndrome in HPV16‐transgenic mice

Santos

Moreira‐Pais

Neto

et al. 2019

Drug Development Research

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The nuclear factor kappa light chain enhancer of activated B cells (NF‐κB) has been implicated in the progression of cancers induced by high‐risk human papillomaviruses (HPV). In cancer patients, NF‐κB is also thought to drive a chronic systemic inflammatory status, leading to cachexia. This study addressed the ability of dimethylaminoparthenolide (DMAPT), a water‐soluble NF‐κB inhibitor, to block the development of HPV‐induced lesions and wasting syndrome in HPV16‐transgenic mice. Mice received DMAPT orally (100 mg/kg/day), once a day, for 6 consecutive weeks. Body weight was monitored weekly along with food and water intake. After 6 weeks the animals were submitted to a grip strength test and sacrificed for specimen collection. Skin samples were analyzed histologically and for expression of NF‐κB‐regulated genes Bcl2 and Bcl2l1. Gastrocnemius muscles were weighted and analyzed for expression of NF‐κB subunits p50, p52, p65, and Rel‐B. DMAPT reduced the incidence of epidermal dysplasia (18.2% versus 33.3% in HPV16+/− untreated mice). This was associated with reduced expression of Bcl2 and Bcl2l1 (p = .0003 and p = .0014, respectively) and reduced neutrophilic infiltration (p = .0339). Treated mice also showed partially preserved bodyweight and strength, which were independent of the expression levels of NF‐κB subunits in skeletal muscle.These results suggest that NF‐κB inhibition may be a valid strategy against HPV‐induced lesions in vivo and warrant further preclinical tests particularly in the set of combination therapies. In addition, the data may support the use of DMAPT to prevent wasting syndrome.

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Inhibition of NF-κB and DNA double-strand break repair by DMAPT sensitizes non-small-cell lung cancers to X-rays

Cited by 23 publications

References 43 publications

Dichloroacetate alters Warburg metabolism, inhibits cell growth, and increases the X-ray sensitivity of human A549 and H1299 NSC lung cancer cells

Dichloroacetate alters Warburg metabolism, inhibits cell growth, and increases the X-ray sensitivity of human A549 and H1299 NSC lung cancer cells

Actinomycin‐D and dimethylamino‐parthenolide synergism in treating human pancreatic cancer cells

Dimethylaminoparthenolide reduces the incidence of dysplasia and ameliorates a wasting syndrome in HPV16‐transgenic mice

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