CoChat
Sign Up
PreprintCited by 0Sirtuins and Resveratrol in MedicineHistone Deacetylase Inhibitors ResearchBioactive Compounds and Antitumor Agents

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells

Open access
Islam, Atikul, Chang, Yu-Chun, Chen, Xiao-Chi, Weng, Chia-Wei, Chen, Chien-Yu, Wang, Che-Wei, Chen, Mu-Kuan, Tikhomirov, Alexander S., Shchekotikhin, Andrey E., Chueh, Pin Ju·2023·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2023.03.29.534690

Preprint — published as 10.7554/elife.87873

Open this paper in CoChat — free accountOpen PDF

Abstract

The antibiotic heliomycin (resistomycin), which is generated from Streptomyces resistomycificus , has multiple activities, including anticancer effects. Heliomycin was first described in the 1960s, but its clinical applications have been hindered by extremely low solubility. A series of 4-aminomethyl derivatives of heliomycin were synthesized to increase water solubility; studies showed that they had anti-proliferative effects, but the drug targets remained unknown. In this study, we conducted cellular thermal shift assays (CETSA) and molecular docking simulations to identify and validate that heliomycin and its water-soluble derivative, 4-(dimethylaminomethyl)heliomycin (designated compound 4-dmH) engaged and targeted with sirtuin-1 (SIRT1) in p53-functional SAS and p53-mutated HSC-3 oral cancer cells. We further addressed the cellular outcome of SIRT1 inhibition by these compounds and found that, in addition to SIRT1, the water-soluble 4-dmH preferentially targeted a tumor-associated NADH oxidase (tNOX, ENOX2). The direct binding of 4-dmH to tNOX decreased the oxidation of NADH to NAD + which diminished NAD + -dependent SIRT1 deacetylase activity, ultimately inducing apoptosis and significant cytotoxicity in both cell types, as opposed to the parental heliomycin-induced autophagy. We also observed that tNOX and SIRT1 were both upregulated in tumor tissues of oral cancer patients compared to adjacent normal tissues, suggesting their clinical relevance. Finally, the better therapeutic efficacy of 4-dmH was confirmed in tumor-bearing mice, which showed greater tNOX and SIRT1 downregulation and tumor volume reduction when treated with 4-dmH compared to heliomycin. Taken together, our in vitro and in vivo findings suggest that the multifaceted properties of water-soluble 4-dmH enable it to offer superior antitumor value compared to parental heliomycin, and indicated that it functions through targeting the tNOX-NAD + -SIRT1 axis to induce apoptosis in oral cancer cells.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/2023.03.29.534690

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Research works printed but not linked: 83

  1. 1958, [New anti-viral antibiotic heliomycin], Antibiotiki (Mosc), 3, 29
  2. Slesarchuk NA , Khvatov EV , Chistov AA , Proskurin GV , Nikitin TD , Lazarevich AI , Ulanovskaya AA , Ulashchik EA , Orlov AA , Jegorov AV et al: Simplistic perylene-related compounds as inhibitors of tick-borne encephalitis virus reproduction. Bioorg Med Chem Lett 2020, 30(10). · DOI
  3. 10.1021/jf305210u · DOI
  4. 2006, [Cytotoxic compounds from the marine actinobacterium], Bioorg Khim, 32, 328
  5. 10.7164/antibiotics.38.113 · DOI
  6. 10.7164/antibiotics.47.136 · DOI
  7. 10.1007/s12275-011-1260-5 · DOI
  8. 2020, Resistomycin, a pentacyclic polyketide, inhibits the growth of triple negative breast cancer cells through induction of apoptosis and mitochondrial dysfunction, Pak J Pharm Sci, 33, 1233
  9. 2018, Isolation of Resistomycin from a Terrestrial Actinomycete with TRAIL Resistance-overcoming Activity, Nat Prod Commun, 13, 65
  10. Abdelfattah MS , Elmallah MIY , Faraag AHI , Hebishy AMS , Ali NH : Heliomycin and tetracinomycin D: anthraquinone derivatives with histone deacetylase inhibitory activity from marine sponge-associated Streptomyces sp SP9. 3 Biotech 2018, 8(6). · DOI
  11. 2021, SIRT1/PGC-1alpha/PPAR-gamma Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer, Front Oncol, 11, 682762, 10.3389/fonc.2021.682762 · DOI
  12. 2021, Trending topics of SIRT1 in tumorigenicity, Biochim Biophys Acta Gen Subj, 1865, 129952, 10.1016/j.bbagen.2021.129952 · DOI
  13. 2021, SIRT1 - a new mammalian substrate of nuclear autophagy, Autophagy, 17, 593, 10.1080/15548627.2020.1860541 · DOI
  14. 10.1038/sj.onc.1210617 · DOI
  15. 10.1038/nrm3293 · DOI · Paper page
  16. 10.1111/j.1474-9726.2010.00548.x · DOI
  17. 10.1111/j.1749-6632.2012.06762.x · DOI
  18. 2018, Narrower insight to SIRT1 role in cancer: A potential therapeutic target to control epithelial-mesenchymal transition in cancer cells, J Cell Physiol, 233, 4443, 10.1002/jcp.26302 · DOI
  19. 10.1073/pnas.0712145105 · DOI
  20. 2020, SRT2183 impairs ovarian cancer by facilitating autophagy, Aging (Albany NY), 12, 24208
  21. 10.1016/j.yexcr.2018.03.023 · DOI
  22. 2021, Recent advances of SIRT1 and implications in chemotherapeutics resistance in cancer, Am J Cancer Res, 11, 5233
  23. 10.1126/science.1233606 · DOI · Paper page
  24. 10.1146/annurev-pharmtox-010715-103715 · DOI
  25. 2022, Antibiotic heliomycin and its water-soluble 4-aminomethylated derivative provoke cell death in T24 bladder cancer cells by targeting sirtuin 1 (SIRT1), Am J Cancer Res, 12, 1042
  26. 2018, Aminomethylation of heliomycin: Preparation and anticancer characterization of the first series of semi-synthetic derivatives, European journal of medicinal chemistry, 143, 1553, 10.1016/j.ejmech.2017.10.055 · DOI
  27. 2021, Water-Soluble Heliomycin Derivatives to Target i-Motif DNA, Journal of Natural Products, 84, 1617, 10.1021/acs.jnatprod.1c00162 · DOI
  28. 10.1021/jm050100l · DOI
  29. 10.1016/j.cell.2013.06.016 · DOI · Paper page
  30. 2022, NAD(+) ameliorates endotoxin-induced acute kidney injury in a sirtuin1-dependent manner via GSK-3beta/Nrf2 signalling pathway, J Cell Mol Med, 26, 1979, 10.1111/jcmm.17222 · DOI
  31. 10.1016/j.tips.2012.05.007 · DOI
  32. 2022, Up-regulation of Sirtuin-1/autophagy signaling in human cerebral ischemia: possible role in caspase-3 mediated apoptosis, Heliyon, 8, e12278, 10.1016/j.heliyon.2022.e12278 · DOI
  33. 2023, HIGD1A links SIRT1 activity to adipose browning by inhibiting the ROS/DNA damage pathway, Cell reports, 42, 112731, 10.1016/j.celrep.2023.112731 · DOI
  34. 10.1016/j.cmet.2011.03.004 · DOI · Paper page
  35. 2015, NAD(+)/NADH metabolism and NAD(+)-dependent enzymes in cell death and ischemic brain injury: current advances and therapeutic implications, Curr Med Chem, 22, 1239, 10.2174/0929867322666150209154420 · DOI
  36. 10.1016/S1097-2765(03)00226-0 · DOI
  37. 2022, Regulation of SIRT1 and Its Roles in Inflammation, Front Immunol, 13, 831168, 10.3389/fimmu.2022.831168 · DOI
  38. 2015, 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, Journal of medicinal chemistry, 58, 9522, 10.1021/acs.jmedchem.5b00859 · DOI
  39. 2020, Capsaicin acts through tNOX (ENOX2) to induce autophagic apoptosis in p53-mutated HSC-3 cells but autophagy in p53-functional SAS oral cancer cells, Am J Cancer Res, 10, 3230
  40. Lin CY , Islam A , Su CJ , Tikhomirov AS , Shchekotikhin AE , Chuang SM , Chueh PJ , Chen YL : 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. Cancers (Basel) 2019, 11(3). · DOI
  41. 2017, Tumor-associated NADH oxidase (tNOX)-NAD+-sirtuin 1 axis contributes to oxaliplatin-induced apoptosis of gastric cancer cells, Oncotarget, 8, 15338, 10.18632/oncotarget.14787 · DOI
  42. 10.1023/A:1022414228013 · DOI
  43. 2003, Adriamycin tolerance in human mesothelioma lines and cell surface NADH oxidase, Life Sci, 73, 1189, 10.1016/S0024-3205(03)00421-1 · DOI
  44. 10.1021/acs.jafc.5b02876 · DOI
  45. Lin MH , Lee YH , Cheng HL , Chen HY , Jhuang FH , Chueh PJ : Capsaicin Inhibits Multiple Bladder Cancer Cell Phenotypes by Inhibiting Tumor-Associated NADH Oxidase (tNOX) and Sirtuin1 (SIRT1). Molecules 2016, 21(7). · DOI
  46. 10.3322/caac.21660 · DOI · Paper page
  47. 2019, The prognostic value of immune checkpoints in oral squamous cell carcinoma, Oral Dis, 25, 1435, 10.1111/odi.12991 · DOI
  48. 10.1016/S1470-2045(17)30458-8 · DOI
  49. 10.1002/ijc.20740 · DOI
  50. 2022, Current trends of targeted therapy for oral squamous cell carcinoma, J Cancer Res Clin Oncol, 148, 2169, 10.1007/s00432-022-04028-8 · DOI
  51. Cheng YX , Chen J , Shi YX , Fang XD , Tang ZG : MAPK Signaling Pathway in Oral Squamous Cell Carcinoma: Biological Function and Targeted Therapy. Cancers 2022, 14(19). · DOI
  52. 2022, Personalized Targeted Therapeutic Strategies against Oral Squamous Cell Carcinoma. An Evidence-Based Review of Literature, Int J Nanomedicine, 17, 4293, 10.2147/IJN.S377816 · DOI
  53. 2022, An insight into therapeutic efficacy of heterocycles as histone-modifying enzyme inhibitors that targets cancer epigenetic pathways, Chem Biol Drug Des, 100, 682, 10.1111/cbdd.14135 · DOI
  54. 2022, Therapeutic potential of tucidinostat, a subtype-selective HDAC inhibitor, in cancer treatment, Front Pharmacol, 13, 932914, 10.3389/fphar.2022.932914 · DOI
  55. 2022, Histone deacetylases modulate resistance to the therapy in lung cancer, Front Genet, 13, 960263, 10.3389/fgene.2022.960263 · DOI
  56. Pan ZJ , Dong H , Huang N , Fang J : Oxidative stress and inflammation regulation of sirtuins: New insights into common oral diseases. Front Physiol 2022, 13. · DOI
  57. 2023, PBX1-SIRT1 Positive Feedback Loop Attenuates ROS-Mediated HF-MSC Senescence and Apoptosis, Stem Cell Rev Rep, 19, 443, 10.1007/s12015-022-10425-w · DOI
  58. Wang X , Lu Y , Tuo Z , Zhou H , Zhang Y , Cao Z , Peng L , Yu D , Bi L : Role of SIRT1/AMPK signaling in the proliferation, migration and invasion of renal cell carcinoma cells. Oncol Rep 2021, 45(6). · DOI
  59. 2018, Everolimus Plus Ku0063794 Regimen Promotes Anticancer Effects against Hepatocellular Carcinoma Cells through the Paradoxical Inhibition of Autophagy, Cancer Res Treat, 50, 1023, 10.4143/crt.2017.085 · DOI
  60. Zhu L , Duan W , Wu GJ , Zhang D , Wang L , Chen D , Chen ZS , Yang B : Protective effect of hydrogen sulfide on endothelial cells through Sirt1-FoxO1-mediated autophagy. Ann Transl Med 2020, 8(23). · DOI
  61. Ran D , Zhou D , Liu G , Ma Y , Ali W , Yu R , Wang Q , Zhao H , Zhu J , Zou H et al: Reactive Oxygen Species Control Osteoblast Apoptosis through SIRT1/PGC-1alpha/P53(Lys382) Signaling, Mediating the Onset of Cd-Induced Osteoporosis. J Agric Food Chem 2023. · DOI
  62. 2020, Role of Sirtuin-1 in Neonatal Hypoxic-Ischemic Encephalopathy and Its Underlying Mechanism, Med Sci Monit, 26, e924544
  63. 2009, Cancer Site-Specific Isoforms of ENOX2 (tNOX), A Cancer-Specific Cell Surface Oxidase, Clinical Proteomics, 5, 46, 10.1007/s12014-008-9016-x · DOI
  64. Sumiyoshi A , Shibata S , Zhelev Z , Miller T , Lazarova D , Aoki I , Obata T , Higashi T , Bakalova R : Targeting Glioblastoma via Selective Alteration of Mitochondrial Redox State. Cancers (Basel) 2022, 14(3). · DOI
  65. 10.1016/j.bbrc.2007.11.025 · DOI
  66. 2016, ENOX2 (or tNOX): a new and old molecule with cancer activity involved in tumor prevention and therapy, J Biol Regul Homeost Agents, 30, 649
  67. 10.1021/jf204869w · DOI
  68. 2021, Capsaicin exerts therapeutic effects by targeting tNOX-SIRT1 axis and augmenting ROS-dependent autophagy in melanoma cancer cells, Am J Cancer Res, 11, 4199
  69. 2016, Update on a tumor-associated NADH oxidase in gastric cancer cell growth, World J Gastroenterol, 22, 2900, 10.3748/wjg.v22.i10.2900 · DOI
  70. Islam A , Su AJ , Zeng ZM , Chueh PJ , Lin MH : Capsaicin Targets tNOX (ENOX2) to Inhibit G1 Cyclin/CDK Complex, as Assessed by the Cellular Thermal Shift Assay (CETSA). Cells 2019, 8(10). · DOI
  71. 2012, Chemotherapeutic agents enhance cell migration and epithelial-to-mesenchymal transition through transient up-regulation of tNOX (ENOX2) protein, Biochim Biophys Acta, 1820, 1744, 10.1016/j.bbagen.2012.07.009 · DOI
  72. 2012, Phosphorylation of serine-504 of tNOX (ENOX2) modulates cell proliferation and migration in cancer cells, Experimental cell research, 318, 1759, 10.1016/j.yexcr.2012.04.021 · DOI
  73. 2004, tNOX is both necessary and sufficient as a cellular target for the anticancer actions of capsaicin and the green tea catechin (-)-epigallocatechin-3-gallate, Biofactors, 20, 235
  74. 10.1016/S0167-4838(01)00286-2 · DOI
  75. 2006, Effect of polyclonal antisera to recombinant tNOX protein on the growth of transformed cells, Biofactors, 28, 119, 10.1002/biof.5520280206 · DOI
  76. 10.1021/jm301431y · DOI
  77. 10.1128/MCB.26.1.28-38.2006 · DOI
  78. 10.1093/NAR/GKAB1061 · DOI · Paper page
  79. 10.1002/jcc.21334 · DOI · Paper page
  80. 10.1007/978-1-4939-2269-7_19 · DOI
  81. 10.1002/jcc.21287 · DOI
  82. 10.1021/ci200227u · DOI
  83. 10.1038/nmeth.3213 · DOI · Paper page

Metadata

Authors
Islam, A., Chang, Y.-C., Chen, X.-C., Weng, C.-W., Chen, C.-Y., Wang, C.-W., Chen, M.-K., Tikhomirov, A. S., Shchekotikhin, A. E., & Chueh, P. J.
Affiliations
  • National Chung Hsing University (TW)
  • Gause Institute of New Antibiotics Russian Academy of Medical Sciences (RU)
Corresponding author
Chueh, Pin Ju
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2023-03-29
DOI
10.1101/2023.03.29.534690
OpenAlex
W4361228095
Cited by
0
References
1
Type
posted content
Language
en
Open access
Licence
cc-by
Locations
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
Keywords
water-soluble derivatives, oral cancer, SIRT1, apoptosis, p53, autophagy, antitumor antibiotics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review