Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cellular Oncology
Published in: Cellular Oncology 3/2016

01-06-2016 | Original Paper

A novel curcumin-like dienone induces apoptosis in triple-negative breast cancer cells

Authors: Elisa Robles-Escajeda, Umashankar Das, Nora M. Ortega, Karla Parra, Giulio Francia, Jonathan R. Dimmock, Armando Varela-Ramirez, Renato J. Aguilera

Published in: Cellular Oncology | Issue 3/2016

Login to get access

Abstract

Purpose

According to the World Health Organization (WHO), breast cancer is the most common cancer affecting women worldwide. In the USA ~12.3 % of all women are expected to be diagnosed with various types of breast cancer, exhibiting varying degrees of therapeutic response rates. Therefore, the identification of novel anti-breast cancer drugs is of paramount importance.

Methods

The 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore was incorporated into a number of cytotoxins. Three of the resulting dienones, 2a, 2b and 2c, were tested for their anti-neoplastic potencies in a variety of human breast cancer-derived cell lines, including the triple negative MDA-MB-231 cell line and its metastatic variant, using a live-cell bio-imaging method. Special emphasis was put on dienone 2c, since its anti-cancer activity and its mode of inflicting cell death have so far not been reported.

Results

We found that all three dienones exhibited potent cytotoxicities towards the breast cancer-derived cell lines tested, whereas significantly lower toxicities were observed towards the non-cancerous human breast cell line MCF-10A. The dienones 2b and 2c exhibited the greatest selective cytotoxicity at submicromolar concentration levels. We found that these two dienones induced phosphatidylserine externalization in MDA-MB-231 cells in a concentration-dependent manner, suggesting that their cytotoxic effect might be mediated by apoptosis. This possibility was confirmed by our observation that the dienone 2c can induce mitochondrial depolarization, caspase-3 activation, cell cycle disruption and DNA fragmentation in MDA-MB-231 cells.

Conclusion

Our findings indicate that dienone 2c uses the mitochondrial/intrinsic pathway to inflict apoptosis in triple negative MDA-MB-231 breast cancer-derived cells. This observation warrants further assessment of dienone 2c as a potential anti-breast cancer drug.
Literature
1.
N. Howlader, A.M. Noone, M. Krapcho, J. Garshell, D. Miller, S.F. Altekruse, C.L. Kosary, M. Yu, J. Ruhl, Z. Tatalovich, A. Mariotto, D.R. Lewis, H.S. Chen, E.J. Feuer, K.A. Cronin, SEER Cancer Statistics Review, 1975-2012, National Cancer Institute, Bethesda, MD, http://​seer.​cancer.​gov/​csr/​1975_​2012/​, based on November 2014 SEER data submission, posted to the SEER web site, April 2015. Accessed Jan 2016
2.
J. Lu, P.S. Steeg, J.E. Price, S. Krishnamurthy, S.A. Mani, J. Reuben, M. Cristofanilli, G. Dontu, L. Bidaut, V. Valero, G.N. Hortobagyi, D. Yu, Breast cancer metastasis: challenges and opportunities. Cancer Res. 69, 4951–4953 (2009)CrossRefPubMed
3.
4.
D.E. Berardi, C. Flumian, P.B. Campodonico, A.J. Urtreger, M.I. Diaz Bessone, A.N. Motter, E.D. Bal de Kier Joffe, E.F. Farias, L.B. Todaro, Myoepithelial and luminal breast cancer cells exhibit different responses to all-trans retinoic acid. Cell. Oncol. 38, 289–305 (2015). doi:10.​1007/​s13402-015-0230-z CrossRef
5.
I. Fkih M’hamed, M. Privat, 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). doi:10.​1007/​s13402-015-0239-3 CrossRef
6.
C.B. Moelans, E.J. Vlug, C. Ercan, P. Bult, H. Buerger, G. Cserni, P.J. van Diest, P.W. Derksen, Methylation biomarkers for pleomorphic lobular breast cancer - a short report. Cell. Oncol. 38, 397–405 (2015). doi:10.​1007/​s13402-015-0241-9 CrossRef
7.
Y. You, H. Li, X. Qin, Y. Zhang, W. Song, Y. Ran, F. Gao, Decreased CDK10 expression correlates with lymph node metastasis and predicts poor outcome in breast cancer patients - a short report. Cell. Oncol. 38, 485–491 (2015). doi:10.​1007/​s13402-015-0246-4 CrossRef
8.
T. Vargo-Gogola, J.M. Rosen, Modelling breast cancer: one size does not fit all. Nat. Rev. Cancer 7, 659–672 (2007)CrossRefPubMed
9.
R. Dent, M. Trudeau, K.I. Pritchard, W.M. Hanna, H.K. Kahn, C.A. Sawka, L.A. Lickley, E. Rawlinson, P. Sun, S.A. Narod, Triple-negative breast cancer: clinical features and patterns of recurrence. Clin. Cancer Res. 13, 4429–4434 (2007)CrossRefPubMed
10.
S. Badve, D.J. Dabbs, S.J. Schnitt, F.L. Baehner, T. Decker, V. Eusebi, S.B. Fox, S. Ichihara, J. Jacquemier, S.R. Lakhani, J. Palacios, E.A. Rakha, A.L. Richardson, F.C. Schmitt, P.-H. Tan, G.M. Tse, B. Weigelt, I.O. Ellis, J.S. Reis-Filho, Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. Mod. Pathol. 24, 157–167 (2011)CrossRefPubMed
11.
R. Cailleau, R. Young, M. Olive, W.J. Reeves Jr., Breast tumor cell lines from pleural effusions. J. Natl. Cancer Inst. 53, 661–674 (1974)PubMed
12.
R. Munoz, S. Man, Y. Shaked, C.R. Lee, J. Wong, G. Francia, R.S. Kerbel, Highly efficacious nontoxic preclinical treatment for advanced metastatic breast cancer using combination oral UFT-cyclophosphamide metronomic chemotherapy. Cancer Res. 66, 3386–3391 (2006)CrossRefPubMed
13.
H.D. Soule, T.M. Maloney, S.R. Wolman, W.D. Peterson Jr., R. Brenz, C.M. McGrath, J. Russo, R.J. Pauley, R.F. Jones, S.C. Brooks, Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res. 50, 6075–6086 (1990)PubMed
14.
E. Robles-Escajeda, A. Martinez, A. Varela-Ramirez, R.A. Sanchez-Delgado, R.J. Aguilera, Analysis of the cytotoxic effects of ruthenium-ketoconazole and ruthenium-clotrimazole complexes on cancer cells. Cell Biol. Toxicol. 29, 431–443 (2013)CrossRefPubMedPubMedCentral
15.
K. Mohankumar, S. Pajaniradje, S. Sridharan, V.K. Singh, L. Ronsard, A.C. Banerjea, B.C. Selvanesan, M.S. Coumar, L. Periyasamy, R. Rajagopalan, Apoptosis induction by an analog of curcumin (BDMC-A) in human laryngeal carcinoma cells through intrinsic and extrinsic pathways. Cell. Oncol. 37, 439–454 (2014). doi:10.​1007/​s13402-014-0207-3 CrossRef
16.
M.A. Pereira, C.J. Grubbs, L.H. Barnes, H. Li, G.R. Olson, I. Eto, M. Juliana, L.M. Whitaker, G.J. Kelloff, V.E. Steele, R.A. Lubet, Effects of the phytochemicals, curcumin and quercetin, upon azoxymethane-induced colon cancer and 7,12-dimethylbenz[a]anthracene-induced mammary cancer in rats. Carcinogenesis 17, 1305–1311 (1996)CrossRefPubMed
17.
T.S. Rao, N. Basu, H.H. Siddiqui, Anti-inflammatory activity of curcumin analogues. Indian J. Med. Res. 75, 574–578 (1982)PubMed
18.
B. Mutus, J.D. Wagner, C.J. Talpas, J.R. Dimmock, O.A. Phillips, R.S. Reid, 1-p-Chlorophenyl-4,4-dimethyl-5-diethylamino-1-penten-3-one hydrobromide, a sulfhydryl-specific compound which reacts irreversibly with protein thiols but reversibly with small molecular weight thiols. Anal. Biochem. 177, 237–243 (1989)CrossRefPubMed
19.
C.P. Page, Integrated pharmacology, 3rd edn. (Elsevier Mosby, Edinburgh, 2006)
20.
U. Das, R.K. Sharma, J.R. Dimmock, 1,5-diaryl-3-oxo-1,4-pentadienes: a case for antineoplastics with multiple targets. Curr. Med. Chem. 16, 2001–2020 (2009)CrossRefPubMedPubMedCentral
21.
G. Chen, D.J. Waxman, Role of cellular glutathione and glutathione S-transferase in the expression of alkylating agent cytotoxicity in human breast cancer cells. Biochem. Pharmacol. 47, 1079–1087 (1994)CrossRefPubMed
22.
J.B. Mitchell, A. Russo, The role of glutathione in radiation and drug induced cytotoxicity. Br. J. Cancer Suppl. 8, 96–104 (1987)PubMedPubMedCentral
23.
J.R. Dimmock, M.P. Padmanilayam, R.N. Puthucode, A.J. Nazarali, N.L. Motaganahalli, G.A. Zello, J.W. Quail, E.O. Oloo, H.B. Kraatz, J.S. Prisciak, T.M. Allen, C.L. Santos, J. Balzarini, E. De Clercq, E.K. Manavathu, A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues. J. Med. Chem. 44, 586–593 (2001)CrossRefPubMed
24.
U. Das, J. Alcorn, A. Shrivastav, R.K. Sharma, E. De Clercq, J. Balzarini, J.R. Dimmock, Design, synthesis and cytotoxic properties of novel 1-[4-(2-alkylaminoethoxy)phenylcarbonyl]-3,5-bis(arylidene)-4-piperidones and related compounds. Eur. J. Med. Chem. 42, 71–80 (2007)CrossRefPubMed
25.
C. Lema, A. Varela-Ramirez, R.J. Aguilera, Differential nuclear staining assay for high-throughput screening to identify cytotoxic compounds. Curr Cell. Biochem. 1, 1–14 (2011)PubMedPubMedCentral
26.
J. Debnath, S.K. Muthuswamy, J.S. Brugge, Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30, 256–268 (2003)CrossRefPubMed
27.
L.M. Nunes, E. Robles-Escajeda, Y. Santiago-Vazquez, N.M. Ortega, C. Lema, A. Muro, G. Almodovar, U. Das, S. Das, J.R. Dimmock, R.J. Aguilera, A. Varela-Ramirez, The gender of cell lines matters when screening for novel anti-cancer drugs. AAPS J. 16, 872–874 (2014)CrossRefPubMedPubMedCentral
28.
A. Varela-Ramirez, M. Costanzo, Y.P. Carrasco, K.H. Pannell, R.J. Aguilera, Cytotoxic effects of two organotin compounds and their mode of inflicting cell death on four mammalian cancer cells. Cell Biol. Toxicol. 27, 159–168 (2011)CrossRefPubMed
29.
E. Robles-Escajeda, D. Lerma, A.M. Nyakeriga, J.A. Ross, R.A. Kirken, R.J. Aguilera, A. Varela-Ramirez, Searching in mother nature for anti-cancer activity: anti-proliferative and pro-apoptotic effect elicited by green barley on leukemia/lymphoma cells. PLoS One 8, e73508 (2013)CrossRefPubMedPubMedCentral
30.
31.
H. Li, H. Zhu, C.J. Xu, J. Yuan, Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491–501 (1998)CrossRefPubMed
32.
D.A. Pedroza, F. De Leon, A. Varela-Ramirez, C. Lema, R.J. Aguilera, S. Mito, The cytotoxic effect of 2-acylated-1,4-naphthohydroquinones on leukemia/lymphoma cells. Biorg. Med. Chem. 22, 842–847 (2014). doi:10.​1016/​j.​bmc.​2013.​12.​007 CrossRef
33.
B. Yadav, S. Taurin, R.J. Rosengren, M. Schumacher, M. Diederich, T.J. Somers-Edgar, L. Larsen, Synthesis and cytotoxic potential of heterocyclic cyclohexanone analogues of curcumin. Biorg. Med. Chem. 18, 6701–6707 (2010)CrossRef
34.
J.-M. Shieh, Y.-C. Chen, Y.-C. Lin, J.-N. Lin, W.-C. Chen, Y.-Y. Chen, C.-T. Ho, T.-D. Way, Demethoxycurcumin inhibits energy metabolic and oncogenic signaling pathways through AMPK activation in triple-negative breast cancer cells. J. Agric. Food Chem. 61, 6366–6375 (2013)CrossRefPubMed
35.
E. Solary, N. Droin, A. Bettaieb, L. Corcos, M.T. Dimanche-Boitrel, C. Garrido, Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies. Leukemia 14, 1833–1849 (2000)CrossRefPubMed
36.
Z. Birsu Cincin, M. Unlu, B. Kiran, E. Sinem Bireller, Y. Baran, B. Cakmakoglu, Anti-proliferative, apoptotic and signal transduction effects of hesperidin in non-small cell lung cancer cells. Cell. Oncol. 38, 195–204 (2015). doi:10.​1007/​s13402-015-0222-z CrossRef
37.
T. Nakaoka, A. Ota, T. Ono, S. Karnan, H. Konishi, A. Furuhashi, Y. Ohmura, Y. Yamada, Y. Hosokawa, Y. Kazaoka, Combined arsenic trioxide-cisplatin treatment enhances apoptosis in oral squamous cell carcinoma cells. Cell. Oncol. 37, 119–129 (2014). doi:10.​1007/​s13402-014-0167-7 CrossRef
38.
L.A. Loeb, D.C. Wallace, G.M. Martin, The mitochondrial theory of aging and its relationship to reactive oxygen species damage and somatic mtDNA mutations. PNAS 102, 18769–18770 (2005)CrossRefPubMedPubMedCentral
39.
B. Westermann, Mitochondrial fusion and fission in cell life and death. Nat. Rev. Mol. Cell Biol. 11, 872–884 (2010)CrossRefPubMed
40.
M. Lahouel, S. Amedah, A. Zellagui, A. Touil, S. Rhouati, F. Benyache, E. Leghouchi, H. Bousseboua, The interaction of new plant flavonoids with rat liver mitochondria: relation between the anti- and pro-oxydant effect and flavonoids concentration. Therapie 61, 347–355 (2006)CrossRefPubMed
41.
B.K. Adams, J. Cai, J. Armstrong, M. Herold, Y.J. Lu, A. Sun, J.P. Snyder, D.C. Liotta, D.P. Jones, M. Shoji, EF24, a novel synthetic curcumin analog, induces apoptosis in cancer cells via a redox-dependent mechanism. Anticancer Drugs 16, 263–275 (2005)CrossRefPubMed
42.
F.H. Igney, P.H. Krammer, Death and anti-death: tumour resistance to apoptosis. Nat. Rev. Cancer 2, 277–288 (2002)CrossRefPubMed
43.
S. Kothakota, T. Azuma, C. Reinhard, A. Klippel, J. Tang, K. Chu, T.J. McGarry, M.W. Kirschner, K. Koths, D.J. Kwiatkowski, L.T. Williams, Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science 278, 294–298 (1997)CrossRefPubMed
44.
J.D. Ly, D.R. Grubb, A. Lawen, The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis 8, 115–128 (2003)CrossRefPubMed
45.
46.
47.
Metadata
Title
A novel curcumin-like dienone induces apoptosis in triple-negative breast cancer cells
Authors
Elisa Robles-Escajeda
Umashankar Das
Nora M. Ortega
Karla Parra
Giulio Francia
Jonathan R. Dimmock
Armando Varela-Ramirez
Renato J. Aguilera
Publication date
01-06-2016
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 3/2016
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-016-0272-x

Other articles of this Issue 3/2016

Cellular Oncology 3/2016 Go to the issue

Original Paper

Tumor-specific promoter-driven adenoviral therapy for insulinoma

Review

Altered primary chromatin structures and their implications in cancer development

Short Communication

Inactivation of CYLD in intestinal epithelial cells exacerbates colitis-associated colorectal carcinogenesis - a short report

Original Paper

Cytotoxicity of allitinib, an irreversible anti-EGFR agent, in a large panel of human cancer-derived cell lines: KRAS mutation status as a predictive biomarker

Original Paper

Small-molecule inhibitors of FGFR, integrins and FAK selectively decrease L1CAM-stimulated glioblastoma cell motility and proliferation

Original Paper

Biomarkers for the identification of precursor polyps of colorectal serrated adenocarcinomas
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits