Synthesis and Characterization of 4,11-Diaminoanthra[2,3-<i>b</i>]furan-5,10-diones: Tumor Cell Apoptosis through tNOX-Modulated NAD<sup>+</sup>/NADH Ratio and SIRT1

Тихомиров, А. С.; Shchekotikhin, Andrey E.; Lee, Yi-Hui; Chen, Yi‐Ann; Yeh, Chia-An; Tatarskiy, Victor V.; Dezhenkova, Lyubov G.; Glazunova, Valeria A.; Balzarini, Jan; Shtil, Alexander A.; Preobrazhenskaya, M. N.; Chueh, Pin Ju

doi:10.1021/acs.jmedchem.5b00859

Cited by 37 publications

(16 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, forced depletion of tNOX by RNA interference in these resistant p53-mutated cells augmented their spontaneous apoptosis, increased their drug sensitivity, and diminished their cell growth [ 9 ]. These findings and those of other studies strongly support the notion that tNOX may be a potential therapeutic drug target [ 14 , 15 , 18 – 21 ]. However, it was unclear whether p53 participates in governing anticancer-drug-induced inhibition of tNOX and subsequent apoptosis of cancer cells.…”

Section: Introductionsupporting

confidence: 88%

Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells

Chen¹,

Islam²,

Yuan³

et al. 2018

J Exp Clin Cancer Res

Self Cite

View full text Add to dashboard Cite

BackgroundOxaliplatin belongs to the platinum-based drug family and has shown promise in treating cancer by binding to DNA to induce cytotoxicity. However, individual patients show diverse therapeutic responses toward oxaliplatin due to yet-unknown underlying mechanisms. We recently established that oxaliplatin also exert its anti-cancer activity in gastric cancer cell lines by targeting tumor-associated NADH oxidase (tNOX), attenuate NAD+ generation and reduce NAD+-dependent sirtuin 1 (SIRT1) deacetylase activity, which in turn enhances p53 acetylation and apoptosis.MethodsIn this study, differential cellular outcomes in response to oxaliplatin exposure of p53-wild-type versus p53-null HCT116 human colon cancer cells were examined. Cell growth profile was determined by cell impedance measurements and apoptosis was analyzed by flow cytometry. The engagement between oxaliplatin and tNOX protein was studied by cellular thermal shift assay. Furthermore, western blot analysis revealed that p53 was important in regulating tNOX expression in these cell lines.ResultsIn p53-wild-type cells, we found that oxaliplatin inhibited cell growth by inducing apoptosis and concurrently down-regulating tNOX at both the transcriptional and translational levels. In p53-null cells, in contrast, oxaliplatin moderately up-regulated tNOX expression and yielded no apoptosis and much less cytotoxicity. Further experiments revealed that in p53-wild-type cells, oxaliplatin enhanced ROS generation and p53 transcriptional activation, leading to down-regulation of the transcriptional factor, POU3F2, which enhances the expression of tNOX. Moreover, the addition of a ROS scavenger reversed the p53 activation, POU3F2 down-regulation, and apoptosis induced by oxaliplatin in p53-wild-type cells. In the p53-null line, on the other hand, oxaliplatin treatment triggered less ROS generation and no p53 protein, such that POU3F2 and tNOX were not down-regulated and oxaliplatin-mediated cytotoxicity was attenuated.ConclusionOur results show that oxaliplatin mediates differential cellular responses in colon cancer cells depending on their p53 status, and demonstrate that the ROS-p53 axis is important for regulating POU3F2 and its downstream target, tNOX. Notably, the depletion of tNOX sensitizes p53-null cells to both spontaneous and oxaliplatin-induced apoptosis. Our work thus clearly shows a scenario in which targeting of tNOX may be a potential strategy for cancer therapy in a p53-inactivated system.

show abstract

Section: Introductionsupporting

confidence: 88%

Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells

Chen¹,

Islam²,

Yuan³

et al. 2018

J Exp Clin Cancer Res

Self Cite

View full text Add to dashboard Cite

show abstract

“…В результате целенаправленных исследований связи структура-активность, проведенных в ФГБНУ НИИНА, было показано, что антра [2,3-b] фуран-3-карбоксамиды являются перспективным классом соединений для дальнейшего поиска химиотерапевтических средств [16,17]. Соединение-лидер этого ряда антрафуран ЛХТА-2034 обладает способностью ингибировать активность нескольких внутриклеточных мишеней, важных для опухолевого роста, включая топоизомеразы I, II и протеинкиназы, и прояв ляет высокую противоопухолевую активность в экспериментах на животных [8]…”

Section: Discussionunclassified

Toxicological characteristic of novel antitumour multitargeted agent anthrafuran

Переверзева

Treschalin

Eremkin

et al. 2017

Rossijskij bioterapevtičeskij žurnal

View full text Add to dashboard Cite

Introduction. One of the modern approaches to development of antitumor drugs is based on oriented search of specific tumor cells molecular targets inhibitors. The application of such therapeutic agents will improve selectivity of action and decrease side effects of antineoplastic therapy. Novel antitumor multitargeted drug anthrafuran (LCTA-2034), obtained in Gause Institute of new antibiotics, represents a derivative of anthra[2,3-b]furan-3-carboxamide. Compound exhibits pronounced antitumor activity in vivo. Objective. The objective of the present study was to investigate the toxicity of LCTA-2034. Materials and methods. Toxicological study was performed in male outbred rats. The drug was administrated intraperitoneally at the total doses of MTD and LD 50 (14 × 3 mg/kg or 14 × 4.5 mg/kg with 24-h interval). Dynamics of body weight, hematological parameters, blood biochemical parameters, electrocardiography and urinalysis were performed for all animals. 5 animals in each group were sacrificed 1 and 30 days post treatment. The mass coefficients of heart, kidneys, liver, spleen and thymus were calculated. The internal organs were subjected to histological evaluation. Results. The results of the study demonstrate that the intraperitoneal injections of LCTA-2034 don't produce any changes in examined clini cal-laboratory parameters. The treatment with LCTA-2034 in total dose of MTD had no effect on morphological structure of the internal organs of rats. The reversible structural damages in liver, kidneys and small intestine were found in group of rats, treated with high dose of the drug. Signs of cardiotoxicity were documented by microscopic pathology observation on day 30 post treatment in individual animals. Conclusion. Dose dependence and reversibility of toxic effects of LCTA-2034 allows us to recommend it to further advance.

show abstract

“…We recently reported the synthesis of a series of novel anti-cancer compounds based on furan-fused anthraquinone derivatives that have different side chains, and showed that these derivatives have high antiproliferative activities against various cancer cell lines, including some with resistance to doxorubicin [8,9,10,11,12]. Biological studies revealed that these derivatives exert cytotoxicity via multiple mechanisms, such as by down-regulating a tumor-associated NADH oxidase (tNOX, ENOX2) and Sirtuin 1 (SIRT1) [8]. The human tNOX gene, located on Xq25-26, encodes a protein of 610 amino acids and is universally expressed in an array of cancer/transformed cells derived from solid tumors [13,14,15,16].…”

Section: Introductionmentioning

confidence: 99%

“…In cancer therapy, it is thought that the suppression of tNOX by various agents (e.g., capsaicin, epigallocatechin gallate, tamoxifen, oxaliplatin) induces apoptosis and attenuates cancer cell growth [19,22,23,24,25]. tNOX converts reduced NADH or hydroquinones to oxidized NAD + [14,15,26], and recent studies have demonstrated that inhibition of tNOX activity reduces the intracellular NAD + level, which in turn impacts NAD + -dependent SIRT1 deacetylase activity and apoptosis [8,25,27].…”

Section: Introductionmentioning

confidence: 99%

Engagement with tNOX (ENOX2) to Inhibit SIRT1 and Activate p53-Dependent and -Independent Apoptotic Pathways by Novel 4,11-Diaminoanthra[2,3-b]furan-5,10-diones in Hepatocellular Carcinoma Cells

Lin

Islam

et al. 2019

Cancers

Self Cite

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the most frequent primary malignancy of the liver and is among the top three causes of cancer-associated death worldwide. However, the clinical use of chemotherapy for HCC has been limited by various challenges, emphasizing the urgent need for novel agents with improved anticancer properties. We recently synthesized and characterized a series of 4,11-diaminoanthra[2,3-b]furan-5,10-dione derivatives that exhibit potent apoptotic activity against an array of cancer cell lines, including variants with multidrug resistance. Their effect on liver cancer cells, however, was unknown. Here, we investigated three selected 4,11-diaminoanthra[2,3-b]furan-5,10-dione derivatives (compounds 1–3) for their cytotoxicity and the underlying molecular mechanisms in wild-type or p53-deficient HCC cells. Cytotoxicity was determined by WST-1 assays and cell impedance measurements and apoptosis was analyzed by flow cytometry. The interaction between compounds and tumor-associated NADH oxidase (tNOX, ENOX2) was studied by cellular thermal shift assay (CETSA). We found that compound 1 and 2 induced significant cytotoxicity in both HepG2 and Hep3B lines. CETSA revealed that compounds 1 and 2 directly engaged with tNOX, leading to a decrease in the cellular NAD+/NADH ratio. This decreased the NAD+-dependent activity of Sirtuin 1 (SIRT1) deacetylase. In p53-wild-type HepG2 cells, p53 acetylation/activation was enhanced, possibly due to the reduction in SIRT1 activity, and apoptosis was observed. In p53-deficient Hep3B cells, the reduction in SIRT1 activity increased the acetylation of c-Myc, thereby reactivating the TRAIL pathway and, ultimately leading to apoptosis. These compounds thus trigger apoptosis in both cell types, but via different pathways. Taken together, our data show that derivatives 1 and 2 of 4,11-diaminoanthra[2,3-b]furan-5,10-diones engage with tNOX and inhibit its oxidase activity. This results in cytotoxicity via apoptosis through tNOX-SIRT1 axis to enhance the acetylation of p53 or c-Myc in HCC cells, depending on their p53 status.

show abstract

Synthesis and Characterization of 4,11-Diaminoanthra[2,3-b]furan-5,10-diones: Tumor Cell Apoptosis through tNOX-Modulated NAD⁺/NADH Ratio and SIRT1

Cited by 37 publications

References 47 publications

Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells

Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells

Toxicological characteristic of novel antitumour multitargeted agent anthrafuran

Engagement with tNOX (ENOX2) to Inhibit SIRT1 and Activate p53-Dependent and -Independent Apoptotic Pathways by Novel 4,11-Diaminoanthra[2,3-b]furan-5,10-diones in Hepatocellular Carcinoma Cells

Contact Info

Product

Resources

About

Synthesis and Characterization of 4,11-Diaminoanthra[2,3-b]furan-5,10-diones: Tumor Cell Apoptosis through tNOX-Modulated NAD+/NADH Ratio and SIRT1

Cited by 37 publications

References 47 publications

Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells

Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells

Toxicological characteristic of novel antitumour multitargeted agent anthrafuran

Engagement with tNOX (ENOX2) to Inhibit SIRT1 and Activate p53-Dependent and -Independent Apoptotic Pathways by Novel 4,11-Diaminoanthra[2,3-b]furan-5,10-diones in Hepatocellular Carcinoma Cells

Contact Info

Product

Resources

About

Synthesis and Characterization of 4,11-Diaminoanthra[2,3-b]furan-5,10-diones: Tumor Cell Apoptosis through tNOX-Modulated NAD⁺/NADH Ratio and SIRT1