Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende
Erweiterte Suche
Anmelden
nach oben
Cellular Oncology
Erschienen in: Cellular Oncology 1/2018

13.11.2017 | Original Paper

Diterpenoid natural compound C4 (Crassin) exerts cytostatic effects on triple-negative breast cancer cells via a pathway involving reactive oxygen species

verfasst von: Cathy E. Richards, Sri H. Vellanki, Yvonne E. Smith, Ann M. Hopkins

Erschienen in: Cellular Oncology | Ausgabe 1/2018

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Triple-negative breast cancers (TNBC) lack expression of three common cell surface receptors, i.e., estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). Accordingly, TNBCs are associated with fewer treatment options and a relatively poor prognosis. Having screened a National Cancer Institute natural compound library, the purpose of this study was to investigate the bioactivity of compound C4 (Crassin) in TNBC cells.

Methods

Cell viability assays were performed in two TNBC cell lines, MDA-MB-231 and 4T1, following C4 treatment in the presence or absence of the antioxidant N-acetyl-L-cysteine (NAC). Phosphorylation of Akt and ERK was assessed by Western blotting. Apoptosis, necrosis, autophagy, necroptosis, ferroptosis and cytostasis assays were performed to explain viability deficits resulting from C4 exposure.

Results

We found that the viability of the TNBC cells tested decreased in a concentration- and time-dependent fashion following C4 treatment. This decrease coincided with an unexpected increase in the expression of the cell survival effectors pAkt and pERK. In addition, we found that both the decreased cell viability and the increased pAkt/pERK levels could be rescued by the antioxidant NAC, suggesting a central role for reactive oxygen species (ROS) in the mechanism of action of C4. Necrosis, apoptosis, necroptosis and ferroptosis could be ruled out as cell death mechanisms. Instead, we found that C4 induced cytostasis downstream of ROS activation. Finally, we observed a synergistic effect between C4 and the chemotherapeutic drug doxorubicin in TNBC cells.

Conclusions

From our in vitro data we conclude that C4 exerts cytostatic effects on triple-negative breast cancer cells via a pathway involving reactive oxygen species. Its potential value in combination with cytotoxic therapies merits deeper investigation in pre-clinical models.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
2.
W.D. Foulkes, I.E. Smith, J.S. Reis-Filho, Triple-negative breast cancer. N. Engl. J. Med. 363, 1938–1948 (2010)CrossRefPubMed
3.
4.
5.
M.C. Wani, H.L. Taylor, M.E. Wall, P. Coggon, A.T. McPhail, Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J. Am. Chem. Soc. 93, 2325–2327 (1971)CrossRefPubMed
6.
H. Parekh, H. Simpkins, The transport and binding of taxol. Gen. Pharmacol. 29, 167–172 (1997)CrossRefPubMed
7.
C. Khanna, M. Rosenberg, D.M. Vail, A review of paclitaxel and novel formulations including those suitable for use in dogs. J. Vet. Intern. Med. 29, 1006–1012 (2015)CrossRefPubMedPubMedCentral
8.
Q.Q. Yuan, S. Tang, W.B. Song, W.Q. Wang, M. Huang, L.J. Xuan, A.-H. Crassins, Diterpenoids from the roots of croton crassifolius. J. Nat. Prod. 80, 254–260 (2017)CrossRefPubMed
9.
S. Donatello, L. Hudson, D.C. Cottell, A. Blanco, I. Aurrekoetxea, M.J. Shelly, P.A. Dervan, M.R. Kell, M. Stokes, A.D. Hill, A.M. Hopkins, An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models. J. Exp. Clin. Cancer Res. 30, 45 (2011)CrossRefPubMedPubMedCentral
10.
S. Nobili, D. Lippi, E. Witort, M. Donnini, L. Bausi, E. Mini, S. Capaccioli, Natural compounds for cancer treatment and prevention. Pharmacol. Res. 59, 365–378 (2009)CrossRefPubMed
11.
N. Hasima, L.I. Aun, M.N. Azmi, A.N. Aziz, E. Thirthagiri, H. Ibrahim, K. Awang, 1′S-1′-acetoxyeugenol acetate: a new chemotherapeutic natural compound against MCF-7 human breast cancer cells. Phytomedicine 17, 935–939 (2010)CrossRefPubMed
12.
A.J. Robles, L. Du, R.H. Cichewicz, S.L. Mooberry, D.N.A. Maximiscin induces damage, activates DNA damage response pathways, and has selective cytotoxic activity against a subtype of triple-negative breast cancer. J. Nat. Prod. 79, 1822–1827 (2016)
13.
E.J. Kim, S.Y. Park, J.Y. Lee, J.H. Park, Fucoidan present in brown algae induces apoptosis of human colon cancer cells. BMC Gastroenterol. 10, 96 (2010)CrossRefPubMedPubMedCentral
14.
H. Yamaguchi, H.G. Wang, The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change. Oncogene 20, 7779–7786 (2001)CrossRefPubMed
15.
G. Song, G. Ouyang, S. Bao, The activation of Akt/PKB signaling pathway and cell survival. J. Cell. Mol. Med. 9, 59–71 (2005)CrossRefPubMed
16.
S.R. Datta, A. Brunet, M.E. Greenberg, Cellular survival: a play in three Akts. Genes Dev. 13, 2905–2927 (1999)CrossRefPubMed
17.
A. Brunet, A. Bonni, M.J. Zigmond, M.Z. Lin, P. Juo, L.S. Hu, M.J. Anderson, K.C. Arden, J. Blenis, M.E. Greenberg, Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999)CrossRefPubMed
18.
I. Dolado, A.R. Nebreda, AKT and oxidative stress team up to kill cancer cells. Cancer Cell 14, 427–429 (2008)CrossRefPubMed
19.
Y.Q. Hou, Y. Yao, Y.L. Bao, Z.B. Song, C. Yang, X.L. Gao, W.J. Zhang, L.G. Sun, C.L. Yu, Y.X. Huang, G.N. Wang, Y.X. Li, Juglanthraquinone C induces intracellular ROS increase and apoptosis by activating the Akt/foxo signal pathway in HCC cells. Oxidative Med. Cell. Longev. 2016, 4941623 (2016)
20.
Q. Liu, J. Qiu, M. Liang, J. Golinski, K. van Leyen, J.E. Jung, Z. You, E.H. Lo, A. Degterev, M.J. Whalen, Akt and mTOR mediate programmed necrosis in neurons. Cell Death Dis. 5, e1084 (2014)CrossRefPubMedPubMedCentral
21.
C. Peyssonnaux, A. Eychene, The Raf/MEK/ERK pathway: new concepts of activation. Biol. Cell. 93, 53–62 (2001)CrossRefPubMed
22.
D.G. Kirsch, A. Doseff, B.N. Chau, D.S. Lim, N.C. de Souza-Pinto, R. Hansford, M.B. Kastan, Y.A. Lazebnik, J.M. Hardwick, Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c. J. Biol. Chem. 274, 21155–21161 (1999)CrossRefPubMed
23.
A.G. Porter, R.U. Janicke, Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 6, 99–104 (1999)CrossRefPubMed
24.
S.J. Dixon, B.R. Stockwell, The role of iron and reactive oxygen species in cell death. Nat. Chem. Biol. 10, 9–17 (2014)CrossRefPubMed
25.
26.
27.
S. Fulda, Regulation of necroptosis signaling and cell death by reactive oxygen species. Biol. Chem. 397, 657–660 (2016)PubMed
28.
H.A. Wahba, H.A. El-Hadaad, Current approaches in treatment of triple-negative breast cancer. Cancer Biol. Med. 12, 106–116 (2015)
29.
G.C. Guo, J.X. Wang, M.L. Han, L.P. Zhang, L. Li, microRNA-761 induces aggressive phenotypes in triple-negative breast cancer cells by repressing TRIM29 expression. Cell. Oncol. 40, 157–166 (2017)
30.
E. Robles-Escajeda, U. Das, N.M. Ortega, K. Parra, G. Francia, J.R. Dimmock, A. Varela-Ramirez, R.J. Aguilera, A novel curcumin-like dienone induces apoptosis in triple-negative breast cancer cells. Cell. Oncol. 39, 265–277 (2016)
31.
I. Fkih, M.P. M’hamed, F. Ponelle, F. Penault-Llorca, A. Kenani, Y.-J. Bignon, Identification of miR-10b, miR-26a, miR-146a and miR-153 as potential triple-negative breast cancer biomarkers. Cell. Oncol. 38, 433–442 (2015)
32.
T.F. Franke, C.P. Hornik, L. Segev, G.A. Shostak, C. Sugimoto, PI3K/Akt and apoptosis: size matters. Oncogene 22, 8983–8998 (2003)CrossRefPubMed
33.
H. Zhou, X.M. Li, J. Meinkoth, R.N. Pittman, Akt regulates cell survival and apoptosis at a postmitochondrial level. J. Cell Biol. 151, 483–494 (2000)CrossRefPubMedPubMedCentral
34.
P.D. Ray, B.W. Huang, Y. Tsuji, Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell. Signal. 24, 981–990 (2012)CrossRefPubMedPubMedCentral
35.
Y. Son, Y.K. Cheong, N.H. Kim, H.T. Chung, D.G. Kang, H.O. Pae, Mitogen-activated protein kinases and reactive oxygen species: how can ROS activate MAPK pathways? J. Signal. Transduct. 2011, 792639 (2011)
36.
S. Cagnol, J.C. Chambard, ERK and cell death: mechanisms of ERK-induced cell death--apoptosis, autophagy and senescence. FEBS J. 277, 2–21 (2010)CrossRefPubMed
37.
R.S. Keshari, A. Verma, M.K. Barthwal, M. Dikshit, Reactive oxygen species-induced activation of ERK and p38 MAPK mediates PMA-induced NETs release from human neutrophils. J. Cell. Biochem. 114, 532–540 (2013)CrossRefPubMed
38.
V. Lobo, A. Patil, A. Phatak, N. Chandra, Free radicals, antioxidants and functional foods: impact on human health. Pharmacogn. Rev. 4, 118–126 (2010)CrossRefPubMedPubMedCentral
39.
40.
A. Valencia, J. Moran, Reactive oxygen species induce different cell death mechanisms in cultured neurons. Free Radic. Biol. Med. 36, 1112–1125 (2004)CrossRefPubMed
41.
F. Ciardiello, R. Caputo, R. Bianco, V. Damiano, G. Pomatico, S. De Placido, A.R. Bianco, G. Tortora, Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin. Cancer Res. 6, 2053–2063 (2000)PubMed
42.
M. Villasana, G. Ochoa, S. Aguilar, Modeling and optimization of combined cytostatic and cytotoxic cancer chemotherapy. Artif. Intell. Med. 50, 163–173 (2010)CrossRefPubMed
43.
S.S. Bacus, A.V. Gudkov, M. Lowe, L. Lyass, Y. Yung, A.P. Komarov, K. Keyomarsi, Y. Yarden, R. Seger, Taxol-induced apoptosis depends on MAP kinase pathways (ERK and p38) and is independent of p53. Oncogene 20, 147–155 (2001)CrossRefPubMed
44.
Y.H. Choi, Y.H. Yoo, Taxol-induced growth arrest and apoptosis is associated with the upregulation of the Cdk inhibitor, p21WAF1/CIP1, in human breast cancer cells. Oncol. Rep. 28, 2163–2169 (2012)CrossRefPubMed
Metadaten
Titel
Diterpenoid natural compound C4 (Crassin) exerts cytostatic effects on triple-negative breast cancer cells via a pathway involving reactive oxygen species
verfasst von
Cathy E. Richards
Sri H. Vellanki
Yvonne E. Smith
Ann M. Hopkins
Publikationsdatum
13.11.2017
Verlag
Springer Netherlands
Erschienen in
Cellular Oncology / Ausgabe 1/2018
Print ISSN: 2211-3428
Elektronische ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-017-0357-1

Weitere Artikel der Ausgabe 1/2018

Cellular Oncology 1/2018 Zur Ausgabe

Report

A new ETV6-NTRK3 cell line model reveals MALAT1 as a novel therapeutic target - a short report

Original Paper

Glycogen synthase kinase-3β mediated regulation of matrix metalloproteinase-9 and its involvement in oral squamous cell carcinoma progression and invasion

Letter to the Editor

Metabolic iodine and tumours

Original Paper

Memory CD4+ T cell subsets in tumor draining lymph nodes of breast cancer patients: A focus on T stem cell memory cells

Original Paper

Serum exosomal miR-301a as a potential diagnostic and prognostic biomarker for human glioma

Report

Implications of FGF19 on sorafenib-mediated nitric oxide production in hepatocellular carcinoma cells - a short report

Neu im Fachgebiet Pathologie

01.04.2024 | Forensische Traumatologie | CME

Theoretische Grundlagen von Explosionen und Explosionsverletzungen

Open Access 22.02.2024 | Pathologie | Originalien

Auswirkungen vorgeschalteter Laborprozesse auf die Digitalisierung histologischer Schnittpräparate

21.02.2024 | Thrombozytopenie | CME

Knochenmarkhistologie bei Zytopenien
Beitrag zur hämatologischen Differenzialdiagnostik

Open Access 21.02.2024 | Fettleber | Originalien

Herausforderungen der Automation bei der quantitativen Auswertung von Leberbiopsien
Automatische Quantifizierung von Leberverfettung