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Cited by 55Natural Compounds in Disease TreatmentNatural product bioactivities and synthesisBioactive Compounds and Antitumor Agents

Prooxidative Activity of Celastrol Induces Apoptosis, DNA Damage, and Cell Cycle Arrest in Drug-Resistant Human Colon Cancer Cells

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Moreira, Helena, Szyjka, Anna, Paliszkiewicz, Kamila, Barg, Ewa·2019·Oxidative Medicine and Cellular Longevity
DOI 10.1155/2019/6793957PMC PMC6710751
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Abstract

Cancer resistance to chemotherapy is closely related to tumor heterogeneity, i.e., the existence of distinct subpopulations of cancer cells in a tumor mass. An important role is assigned to cancer stem cells (CSCs), a small subset of cancer cells with high tumorigenic potential and capacity of self-renewal and differentiation. These properties of CSCs are sustained by the ability of those cells to maintain a low intracellular reactive oxygen species (ROS) levels, via upregulation of ROS scavenging systems. However, the accumulation of ROS over a critical threshold disturbs CSCs—redox homeostasis causing severe cytotoxic consequences. In the present study, we investigated the capacity of celastrol, a natural pentacyclic triterpenoid, to induce the formation of ROS and, consequently, cell death of the colon cancer cells with acquired resistant to cytotoxic drugs (LOVO/DX cell line). LOVO/DX cells express several important stem-like cell features, including a higher frequency of side population (SP) cells, higher expression of multidrug resistant proteins, overexpression of CSC-specific cell surface marker (CD44), increased expression of DNA repair gene (PARP1), and low intracellular ROS level. We found that celastrol, at higher concentrations (above 1 μ M), significantly increased ROS amount in LOVO/DX cells at both cytoplasmic and mitochondrial levels. This prooxidant activity was associated with the induction of DNA double-strand breaks (DSBs) and apoptotic/necrotic cell death, as well as with inhibition of cell proliferation by S phase cell cycle arrest. Coincubation with NAC, a ROS scavenger, completely reversed the above effects. In summary, our results provide evidence that celastrol exhibits effective cytotoxic effects via ROS-dependent mechanisms on drug-resistant colon cancer cells. These findings strongly suggest the potential of celastrol to effectively kill cancer stem-like cells, and thus, it is a promising agent to treat severe, resistant to conventional therapy, colon cancers.

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References 41 · Cited by 55

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  1. [1]Boonstra J. Post J. A. Molecular events associated with reactive oxygen species and cell cycle progression in mammalian cells Gene 2004 337 1 13 10.1016/j.gene.2004.04.032 2-s2.0-3242752786 15276197 · DOI
  2. [2]Phaniendra A. Jestadi D. B. Periyasamy L. Free radicals: properties, sources, targets, and their implication in various diseases Indian Journal of Clinical Biochemistry 2015 30 1 11 26 10.1007/s12291-014-0446-0 2-s2.0-84961291449 25646037 PMC4310837 · DOI · Paper page
  3. [3]Dikalov S. I. Harrison D. G. Methods for detection of mitochondrial and cellular reactive oxygen species Antioxidants & Redox Signaling 2014 20 2 372 382 10.1089/ars.2012.4886 2-s2.0-84891778532 22978713 PMC3887411 · DOI
  4. [4]Ding S. Li C. Cheng N. Cui X. Xu X. Zhou G. Redox regulation in cancer stem cells Oxidative Medicine and Cellular Longevity 2015 2015 11 750798 10.1155/2015/750798 2-s2.0-84934891604 PMC4529979 26273424 · DOI
  5. [5]Schumacker P. T. Reactive oxygen species in cancer: a dance with the devil Cancer Cell 2015 27 2 156 157 10.1016/j.ccell.2015.01.007 2-s2.0-84922763809 25670075 · DOI
  6. [7]Haklar G. Sayin-Özveri E. Yüksel M. Aktan A. Ö. Yalçin A. S. Different kinds of reactive oxygen and nitrogen species were detected in colon and breast tumors Cancer Letters 2001 165 2 219 224 10.1016/S0304-3835(01)00421-9 2-s2.0-0035953855 11275372 · DOI
  7. [8]Liu J. Wang Z. Increased oxidative stress as a selective anticancer therapy Oxidative Medicine and Cellular Longevity 2015 2015 12 294303 10.1155/2015/294303 2-s2.0-84939147804 26273420 PMC4529973 · DOI
  8. [9]Wang H. Gao Z. Liu X. Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance Nature Communications 2018 9 1 p. 562 10.1038/s41467-018-02915-8 2-s2.0-85041930721 29422620 PMC5805731 · DOI
  9. [10]Maiti A. K. Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells The Pharmacogenomics Journal 2010 10 2 94 104 10.1038/tpj.2009.49 2-s2.0-77950023644 19918261 · DOI
  10. [11]Kobayashi C. I. Suda T. Regulation of reactive oxygen species in stem cells and cancer stem cells Journal of Cellular Physiology 2012 227 2 421 430 10.1002/jcp.22764 2-s2.0-82155171284 21448925 · DOI
  11. [12]Shi X. Zhang Y. Zheng J. Pan J. Reactive oxygen species in cancer stem cells Antioxidants & Redox Signaling 2012 16 11 1215 1228 10.1089/ars.2012.4529 2-s2.0-84859829553 22316005 PMC3324813 · DOI
  12. [13]Wang L. Zuo X. Xie K. Wei D. The role of CD44 and cancer stem cells Methods in Molecular Biology 2018 31 42 10.1007/978-1-4939-7401-6_3 2-s2.0-85030750690 28986884 · DOI
  13. [14]Yadav V. R. Prasad S. Sung B. Kannappan R. Aggarwal B. B. Targeting inflammatory pathways by triterpenoids for prevention and treatment of cancer Toxins 2010 2 10 2428 2466 10.3390/toxins2102428 2-s2.0-79952084572 22069560 PMC3153165 · DOI · Paper page
  14. [15]Amirruddin N. S. Kumar A. P. Teo A. K. K. Sethi G. Role of celastrol in chemosensitization of cancer Role of Nutraceuticals in Chemoresistance to Cancer, Volume 2 2017 Academic Press 141 150 10.1016/b978-0-12-812373-7.00007-3 · DOI
  15. [16]Yadav P. Jaswal V. Sharma A. Celastrol as a pentacyclic triterpenoid with chemopreventive properties Pharmaceutical Patent Analyst 2018 7 4 155 167 10.4155/ppa-2017-0035 2-s2.0-85054541844 29882724 · DOI
  16. [17]Chen S. R. Dai Y. Zhao J. Lin L. Wang Y. Wang Y. A mechanistic overview of triptolide and celastrol, natural products from Tripterygium wilfordii Hook F Frontiers in Pharmacology 2018 9 p. 104 10.3389/fphar.2018.00104 2-s2.0-85042124570 PMC5817256 29491837 · DOI
  17. [18]Cascão R. Fonseca J. E. Moita L. F. Celastrol: a spectrum of treatment opportunities in chronic diseases Frontiers in Medicine 2017 4 p. 69 10.3389/fmed.2017.00069 2-s2.0-85037138841 PMC5471334 28664158 · DOI
  18. [19]Han X. Sun S. Zhao M. Celastrol stimulates hypoxia-inducible factor-1 activity in tumor cells by initiating the ros/akt/p70s6k signaling pathway and enhancing hypoxia-inducible factor-1α protein synthesis PLoS One 2014 9 11, article e112470 10.1371/journal.pone.0112470 2-s2.0-84911420350 25383959 PMC4226555 · DOI
  19. [20]Chen G. Zhang X. Zhao M. Celastrol targets mitochondrial respiratory chain complex I to induce reactive oxygen species-dependent cytotoxicity in tumor cells BMC Cancer 2011 11 1 p. 170 10.1186/1471-2407-11-170 2-s2.0-79955855304 PMC3112161 21569548 · DOI
  20. [21]Li H. Y. Zhang J. Sun L. L. Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells: an in vitro and in vivo study Cell Death & Disease 2015 6 1, article e1604 10.1038/cddis.2014.543 2-s2.0-84927611106 PMC4669742 25611379 · DOI
  21. [22]Lee J. H. Won Y. S. Park K. H. Celastrol inhibits growth and induces apoptotic cell death in melanoma cells via the activation ROS-dependent mitochondrial pathway and the suppression of PI3K/AKT signaling Apoptosis 2012 17 12 1275 1286 10.1007/s10495-012-0767-5 2-s2.0-84872054236 23065091 · DOI
  22. [23]Xu L.-N. Zhao N. Chen J.-Y. Celastrol inhibits the growth of ovarian cancer cells in vitro and in vivo Frontiers in Oncology 2019 9 2 10.3389/fonc.2019.00002 2-s2.0-85063297534 PMC6360154 30746340 · DOI
  23. [24]Seo H. R. Seo W. D. Pyun B. J. Radiosensitization by celastrol is mediated by modification of antioxidant thiol molecules Chemico-Biological Interactions 2011 193 1 34 42 10.1016/j.cbi.2011.04.009 2-s2.0-79959933122 21570383 · DOI
  24. [25]Eruslanov E. Kusmartsev S. Identification of ROS using oxidized DCFDA and flow-cytometry Methods in Molecular Biology 2010 594 57 72 10.1007/978-1-60761-411-1_4 2-s2.0-77950366686 20072909 · DOI
  25. [26]Slezak A. Moreira H. Szyjka A. Oszmianski J. Gasiorowski K. Condition of prooxidant activity of cistus and pomegranate polyphenols in V79 cell cultures Acta Poloniae Pharmaceutica 2017 74 2 670 678 29624273
  26. [27]Dickinson B. C. Lin V. S. Chang C. J. Preparation and use of MitoPY1 for imaging hydrogen peroxide in mitochondria of live cells Nature Protocols 2013 8 6 1249 1259 10.1038/nprot.2013.064 2-s2.0-84879364681 23722262 PMC4096497 · DOI
  27. [28]Szeberenyl J. Analysis of the cell cycle by flow cytometry Biochemistry and Molecular Biology Education 2007 35 2 153 154 10.1002/bmb.41 2-s2.0-34147192547 21591077 · DOI
  28. [29]Kataoka Y. Bindokas V. P. Duggan R. C. Murley J. S. Grdina D. J. Flow cytometric analysis of phosphorylated histone H2AX following exposure to ionizing radiation in human microvascular endothelial cells Journal of Radiation Research 2006 47 3/4 245 257 10.1269/jrr.0628 2-s2.0-34548447146 16960336 · DOI
  29. [30]León-González A. J. Auger C. Schini-Kerth V. B. Pro-oxidant activity of polyphenols and its implication on cancer chemoprevention and chemotherapy Biochemical Pharmacology 2015 98 3 371 380 10.1016/j.bcp.2015.07.017 2-s2.0-84947035936 26206193 · DOI
  30. [32]Kannaiyan R. Shanmugam M. K. Sethi G. Molecular targets of celastrol derived from thunder of god vine: potential role in the treatment of inflammatory disorders and cancer Cancer Letters 2011 303 1 9 20 10.1016/j.canlet.2010.10.025 2-s2.0-79951853010 21168266 · DOI
  31. [33]Broggini M. Grandi M. Ubezio P. Geroni C. Giuliani F. C. D'Incalci M. Intracellular doxorubicin concentrations and drug-induced DNA damage in a human colon adenocarcinoma cell line and in a drug-resistant subline Biochemical Pharmacology 1988 37 23 4423 4431 10.1016/0006-2952(88)90656-9 2-s2.0-0024208685 3202888 · DOI
  32. [34]Moreira H. Szyjka A. Gąsiorowski K. Chemopreventive activity of celastrol in drug-resistant human colon carcinoma cell cultures Oncotarget 2018 9 30 21211 21223 10.18632/oncotarget.25014 2-s2.0-85045833818 29765532 PMC5940375 · DOI
  33. [36]Preya U. H. Lee K. T. Kim N. J. Lee J. Y. Jang D. S. Choi J. H. The natural terthiophene α-terthienylmethanol induces S phase cell cycle arrest of human ovarian cancer cells via the generation of ROS stress Chemico-Biological Interactions 2017 272 72 79 10.1016/j.cbi.2017.05.011 2-s2.0-85019427056 28506552 · DOI
  34. [37]Peng B. Xu L. Cao F. HSP90 inhibitor, celastrol, arrests human monocytic leukemia cell U937 at G0/G1 in thiol-containing agents reversible way Molecular Cancer 2010 9 1 p. 79 10.1186/1476-4598-9-79 2-s2.0-77950818403 PMC2873437 20398364 · DOI
  35. [39]Huang X. Okafuji M. Traganos F. Luther E. Holden E. Darzynkiewicz Z. Assessment of histone H2AX phosphorylation induced by DNA topoisomerase I and II inhibitors topotecan and mitoxantrone and by the DNA cross-linking agent cisplatin Cytometry 2004 58A 2 99 110 10.1002/cyto.a.20018 15057963 · DOI
  36. [40]Taniguchi H. Moriya C. Igarashi H. Cancer stem cells in human gastrointestinal cancer Cancer Science 2016 107 11 1556 1562 10.1111/cas.13069 2-s2.0-84997796170 27575869 PMC5132287 · DOI
  37. [41]Nagano O. Okazaki S. Saya H. Redox regulation in stem-like cancer cells by CD44 variant isoforms Oncogene 2013 32 44 5191 5198 10.1038/onc.2012.638 2-s2.0-84887043495 23334333 · DOI

Authors
Moreira, H., Szyjka, A., Paliszkiewicz, K., & Barg, E.
Affiliations
Wroclaw Medical University (PL)
Corresponding author
Moreira, Helena
ORCID
Venue
Oxidative Medicine and Cellular Longevity
Publisher
Wiley
Published
2019-08-14
Volume
2019
Pages
1-12
ISSN
  • 1942-0994 (ISSN-L)
  • 1942-0900
DOI
10.1155/2019/6793957
PMC
PMC6710751
OpenAlex
W2968267298
Cited by
55
References
41
Citations by year
2026: 3 · 2025: 7 · 2024: 11 · 2023: 9 · 2022: 6 · 2021: 12 · 2020: 6 · 2019: 1
FWCI
8.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Oxidative Medicine and Cellular Longevity (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Wroclaw Medical University (ST.D130.16.009)
Topics
  • Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Natural product bioactivities and synthesis
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
Keywords
celastrol, pentacyclic triterpenes, colon cancer, chemoresistance, cancer stem cells, reactive oxygen species, pro-oxidant activity, apoptosis, DNA double-strand breaks, cell cycle arrest, S phase arrest, side population cells, CD44, multidrug resistance protein, PARP1, N-acetylcysteine
MeSH terms
Colonic Neoplasms, DNA Damage, Humans, Triterpenes, Apoptosis, Tripterygium, Pentacyclic Triterpenes, Cell Cycle Checkpoints

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