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Cancer Chemotherapy and Pharmacology

Published in:

01-08-2010 | Original Article

Synergistic interactions between aminoflavone, paclitaxel and camptothecin in human breast cancer cells

Authors: Kathryn E. Reinicke, Mary J. Kuffel, Matthew P. Goetz, Matthew M. Ames

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2010

Abstract

Purpose

Aminoflavone is a unique DNA damaging agent currently undergoing phase I evaluation in a prodrug form (AFP464). In anticipation of combination regimens, interactions between aminoflavone and several anticancer drugs were investigated in MCF-7 breast cancer cells to determine whether synergistic cancer cell killing effects were observed.

Methods

Colony formation assays were performed to assess the effect of combining aminoflavone with a variety of anticancer drugs. Changes in initial uptake, retention or efflux of aminoflavone and the second agent were compared to the behavior of drugs alone. Key features required for aminoflavone activity in cell culture models were also explored, focusing on the obligatory induction of CYP1A1/1A2 and binding of reactive aminoflavone metabolites to tumor cell total macromolecules and DNA.

Results

Aminoflavone was synergistic when co-incubated with paclitaxel, camptothecin or SN38. Uptake of neither aminoflavone nor any of the other three compounds was altered in combination incubations. Paclitaxel did not inhibit DNA binding of aminoflavone metabolites, while camptothecin did. Aminoflavone-induced CYP1A1 induction was observed in the presence of camptothecin or paclitaxel.

Conclusions

Aminoflavone is a promising therapeutic agent for breast cancer due to its unique mechanism of action compared to commonly used drugs. Combined treatments utilizing aminoflavone in conjunction with paclitaxel or camptothecin may provide an even greater cytotoxic effect than achieved with aminoflavone alone.

Akama T, Shida Y, Sugaya T, Ishida H, Gomi K, Kasai M (1996) Novel 5-aminoflavone derivatives as specific antitumor agents in breast cancer. J Med Chem 39:3461–3469CrossRefPubMed

Alley PE (1999) Rabbit news and research quarterly. Can Vet J 40:89PubMed

Weinstein JN, Myers TG, O’Connor PM, Friend SH, Fornace AJ Jr, Kohn KW, Fojo T, Bates SE, Rubinstein LV, Anderson NL, Buolamwini JK, van Osdol WW, Monks AP, Scudiero DA, Sausville EA, Zaharevitz DW, Bunow B, Viswanadhan VN, Johnson GS, Wittes RE, Paull KD (1997) An information-intensive approach to the molecular pharmacology of cancer. Science 275:343–349CrossRefPubMed

Kuffel MJ, Schroeder JC, Pobst LJ, Naylor S, Reid JM, Kaufmann SH, Ames MM (2002) Activation of the antitumor agent aminoflavone (nsc 686288) is mediated by induction of tumor cell cytochrome p450 1a1/1a2. Mol Pharmacol 62:143–153CrossRefPubMed

Pobst LJ, Ames MM (2006) Cyp1a1 activation of aminoflavone leads to DNA damage in human tumor cell lines. Cancer Chemother Pharmacol 57:569–576CrossRefPubMed

McLean L, Soto U, Agama K, Francis J, Jimenez R, Pommier Y, Sowers L, Brantley E (2008) Aminoflavone induces oxidative DNA damage and reactive oxidative species-mediated apoptosis in breast cancer cells. Int J Cancer 122:1665–1674CrossRefPubMed

Meng LH, Kohlhagen G, Liao ZY, Antony S, Sausville E, Pommier Y (2005) DNA-protein cross-links and replication-dependent histone h2ax phosphorylation induced by aminoflavone (nsc 686288), a novel anticancer agent active against human breast cancer cells. Cancer Res 65:5337–5343CrossRefPubMed

Forastiere AA, Shank D, Neuberg D, SGt Taylor, DeConti RC, Adams G (1998) Final report of a phase ii evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck: an eastern cooperative oncology group trial (pa390). Cancer 82:2270–2274CrossRefPubMed

Tan EH, Khoo KS, Wee J, Fong KW, Lee KS, Lee KM, Chua ET, Tan T, Khoo-Tan HS, Yang TL, Au E, Tao M, Ong YK, Chua EJ (1999) Phase ii trial of a paclitaxel and carboplatin combination in asian patients with metastatic nasopharyngeal carcinoma. Ann Oncol 10:235–237CrossRefPubMed

10.

Holmes FA, Walters RS, Theriault RL, Forman AD, Newton LK, Raber MN, Buzdar AU, Frye DK, Hortobagyi GN (1991) Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83:1797–1805PubMed

11.

Reichman BS, Seidman AD, Crown JP, Heelan R, Hakes TB, Lebwohl DE, Gilewski TA, Surbone A, Currie V, Hudis CA et al (1993) Paclitaxel and recombinant human granulocyte colony-stimulating factor as initial chemotherapy for metastatic breast cancer. J Clin Oncol 11:1943–1951PubMed

12.

Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98CrossRefPubMed

13.

Ettinger DS, Finkelstein DM, Sarma RP, Johnson DH (1995) Phase II study of paclitaxel in patients with extensive-disease small-cell lung cancer: an eastern cooperative oncology group study. J Clin Oncol 13:1430–1435PubMed

14.

McGuire WP, Rowinsky EK, Rosenshein NB, Grumbine FC, Ettinger DS, Armstrong DK, Donehower RC (1989) Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111:273–279PubMed

15.

Einzig AI, Wiernik PH, Sasloff J, Runowicz CD, Goldberg GL (1992) Phase II study and long-term follow-up of patients treated with taxol for advanced ovarian adenocarcinoma. J Clin Oncol 10:1748–1753PubMed

16.

Sarosy G, Kohn E, Stone DA, Rothenberg M, Jacob J, Adamo DO, Ognibene FP, Cunnion RE, Reed E (1992) Phase I study of taxol and granulocyte colony-stimulating factor in patients with refractory ovarian cancer. J Clin Oncol 10:1165–1170PubMed

17.

McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M (1996) Cyclophosphamide and cisplatin versus paclitaxel and cisplatin: a phase III randomized trial in patients with suboptimal stage iii/iv ovarian cancer (from the gynecologic oncology group). Semin Oncol 23:40–47PubMed

18.

Spratlin J, Sawyer MB (2007) Pharmacogenetics of paclitaxel metabolism. Crit Rev Oncol Hematol 61:222–229CrossRefPubMed

19.

Tubiana-Hulin M (2005) How to maximize the efficacy of taxanes in breast cancer. Cancer Treat Rev 31(Suppl 4):S3–9CrossRefPubMed

20.

Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L (2003) Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983CrossRefPubMed

21.

Urasaki Y, Laco G, Takebayashi Y, Bailly C, Kohlhagen G, Pommier Y (2001) Use of camptothecin-resistant mammalian cell lines to evaluate the role of topoisomerase I in the antiproliferative activity of the indolocarbazole, nb-506, and its topoisomerase I binding site. Cancer Res 61:504–508PubMed

22.

Gupta M, Fujimori A, Pommier Y (1995) Eukaryotic DNA topoisomerases i. Biochim Biophys Acta 1262:1–14PubMed

23.

Becerra CR, Verma UN, Tran HT, Tavana D, Williams NS, Frenkel EP (2008) Phase I dose escalation study with irinotecan, capecitabine, epirubicin, and granulocyte colony-stimulating factor support for patients with solid malignancies. Am J Clin Oncol 31:219–225CrossRefPubMed

24.

Mrozek E, Kolesar J, Young D, Allen J, Villalona-Calero M, Shapiro CL (2008) Phase II study of sequentially administered low-dose mitomycin-c (mmc) and irinotecan (cpt-11) in women with metastatic breast cancer (mbc). Ann Oncol 19:1417–1422CrossRefPubMed

25.

Perez EA, Hillman DW, Mailliard JA, Ingle JN, Ryan JM, Fitch TR, Rowland KM, Kardinal CG, Krook JE, Kugler JW, Dakhil SR (2004) Randomized phase ii study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol 22:2849–2855CrossRefPubMed

26.

Taguchi T, Yoshida Y, Izuo M, Ishida T, Ogawa M, Nakao I, Tominaga T, Ohkawa T, Oguro M, Yoshida M et al (1994) An early phase II study of cpt-11 (irinotecan hydrochloride) in patients with advanced breast cancer. Gan To Kagaku Ryoho 21:83–90PubMed

27.

Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55CrossRefPubMed

28.

Ernster L, Danielson L, Ljunggren M (1962) Dt diaphorase. I. Purification from the soluble fraction of rat-liver cytoplasm, and properties. Biochim Biophys Acta 58:171–188CrossRefPubMed

29.

Pommier Y (2006) Topoisomerase I inhibitors: Camptothecins and beyond. Nat Rev Cancer 6:789–802CrossRefPubMed

30.

Weaver BA, Cleveland DW (2005) Decoding the links between mitosis, cancer, and chemotherapy: the mitotic checkpoint, adaptation, and cell death. Cancer Cell 8:7–12CrossRefPubMed

31.

Meng LH, Shankavaram U, Chen C, Agama K, Fu HQ, Gonzalez FJ, Weinstein J, Pommier Y (2006) Activation of aminoflavone (nsc 686288) by a sulfotransferase is required for the antiproliferative effect of the drug and for induction of histone gamma-h2ax. Cancer Res 66:9656–9664CrossRefPubMed

32.

Oberlies NH, Kroll DJ (2004) Camptothecin and taxol: historic achievements in natural products research. J Nat Prod 67:129–135CrossRefPubMed

33.

Desai SD, Li TK, Rodriguez-Bauman A, Rubin EH, Liu LF (2001) Ubiquitin/26s proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells. Cancer Res 61:5926–5932PubMed

Title: Synergistic interactions between aminoflavone, paclitaxel and camptothecin in human breast cancer cells
Authors: Kathryn E. Reinicke
Mary J. Kuffel
Matthew P. Goetz
Matthew M. Ames
Publication date: 01-08-2010
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2010
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-009-1198-z

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Abstract

Purpose

Methods

Results

Conclusions

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