nach oben

Investigational New Drugs

Erschienen in:

01.04.2009 | PRECLINICAL STUDIES

Suppressive effects of novel derivatives prepared from Aconitum alkaloids on tumor growth

verfasst von: Masaharu Hazawa, Koji Wada, Kenji Takahashi, Takao Mori, Norio Kawahara, Ikuo Kashiwakura

Erschienen in: Investigational New Drugs | Ausgabe 2/2009

Einloggen, um Zugang zu erhalten

Summary

Little information has so far been reported regarding the antiproliferative properties of Aconitum alkaloids against human tumor cells despite of their intense toxicities. In the present study, the antitumor properties and radiation sensitizing effects were investigated by various types of novel derivatives prepared from Aconitum alkaloids. The antitumor properties were investigated against human tumor cell lines, A172, A549, HeLa and Raji, respectively, by a cell growth, a clonogenic assay, cell cycle distribution, cell cycle related molecules and γH2AX expression. The novel compounds derived from C₂₀-diterupenoid alkaloids showed a significantly suppressive effect in all cell lines. In contrast, natural C₁₉-norditerpenoid alkaloids and their derivatives showed either no effect or only a slight effect. One of the compounds also showed radiosensitizing properties on A549 cells. These effects are not related to either the cell cycle distribution, the enhancement of apoptosis or the γH2AX expression. Novel derivatives prepared from Aconitum alkaloids, not but natural alkaloids, clearly showed anti-proliferative activity in human tumor cell lines.

Haveman J, Castro Kreder N, Rodermond HM et al (2004) Cellular response of X-ray sensitive hamster mutant cell lines to gemcitabine, cisplatin and 5-fluorouracil. Oncol Rep 12:187–192PubMed

Didelot C, Mirjolet JF, Barberi-Heyob M (2002) Radiation could induce p53-independent and cell cycle-unrelated apoptosis in 5-fluorouracil radiosensitized head and neck carcinoma cells. Can J Physiol Pharmacol 80:638–643PubMedCrossRef

Pauwels B, Korst AE, Andriessen V et al (2005) Unraveling the mechanism of radiosensitization by gemcitabine: the role of TP53. Radiat Res 164:642–650PubMedCrossRef

Zhang M, Boyer M, Rivory L et al (2004) Radiosensitization of vinorelbine and gemcitabine in NCL-H460 non-small-cell lung cancer cells. Int J Radiat Oncol Biol Phys 58:33–60

Baumann M, Krause M (2004) Targeting the epidermal growth factor receptor in radiotherapy: radiobiological mechanisms, preclinical and clinical results. Radiother Oncol 72:257–266PubMedCrossRef

Kvols LK (2005) Radiation sensitizers: a selective review of molecules targeting DNA and non-DNA targets. J Nucl Med 46:187S–190SPubMed

Sonnemann J, Gekeler V, Ahibrecht K et al (2004) Down-regulation of protein kinase Ceta by antisense oligonucleotides sensitises A549 lung cancer cells to vincristine and paclitaxel. Cancer Lett 209:177–185PubMedCrossRef

Qing C, Jiang C, Zhang JS et al (2001) Induction of apoptosis in human leukemia K-562 and gastric carcinoma SGC-7901 cells by salvicine, a novel anticancer compound. Anticancer Drugs 12:51–56PubMedCrossRef

Meg LH, Zhang JS, Ding J (2001) Salvicine, a novel DNA topoisomerase II inhibitor, exerting its effects by trapping enzyme-DNA cleavage complexes. Biochem Pharmacol 62:733–741CrossRef

10.

Yildiz F, Perez R, Redpath JL (2000) Paclitaxel exposure time determines the nature of interaction with radiation in HeLa cells: the role of apoptosis. Eur J Cancer 36:1426–1532PubMedCrossRef

11.

Chan TY (1994) Aconitine poisoning: a global perspective. Vet Hum Toxicol 36:326–328PubMed

12.

Feldkamp A, Koster B, Weber HP (1991) Fatal poisoning caused by aconitine monk's hood (Aconitum napellus). Monatsschr Kinderheilkd 139:366–367PubMed

13.

Negulyaev Yu A, Vedernikova EA, Savokhina GA (1990) Aconitine-induced modification of signal sodium channels in neuroblastoma cell membrane. Gen Physiol Biophys Commun 9:167–176

14.

Fu M, Wu M, Wang JF et al (2007) Disruption of the intracellular Ca2⁺ homeostasis in the cardiac excitation–concentration coupling is a crucial mechanism of arrhythmic toxicity in aconitine-induced cardiomyocytes. Biochem Biophys Res Commun 23:929–936CrossRef

15.

Wada K, Ishizuki S, Mori T et al (1998) Effects of Aconitum alkaloid kobusine and pseudokobusine derivatives on cutaneous blood flow in mice. Biol Pharm Bull 21:140–146PubMed

16.

Wada K, Ishizuki S, Mori T et al (2000) Effects of Aconitum alkaloid kobusine and pseudokobusine derivatives on cutaneous blood flow in mice; II. Biol Pharm Bull 23:607–615PubMed

17.

Wada K, Ishizuki S, Mori T et al (1997) Effects of alkaloids from Aconitum yesoense var. macroyesoense on cutaneous blood flow in mice. Biol Pharm Bull 20:978–982PubMed

18.

Wada K, Bando H, Amiya T (1985) Two new C₂₀-diterpenoid alkaloids from Aconitum yesoense var. macroyesoense (NAKAI) TAMURA, structures of dehydrolucidusculine and N-deethyldehydrolucidusculine. Heterocycles 23:2473–2477

19.

Bando H, Wada K, Amiya T et al (1987) Studies on Aconitum species V. Constituents of Aconitum yesoense var. macroyesoense (NAKAI) TAMURA. Heterocycles 26:2623–2637

20.

Wada K, Bando H, Amiya T (1988) Studies on Aconitum species VI. Yesoline, a new C₂₀-diterpenoid alkaloid from Aconitum yesoense var. macroyesoense (NAKAI) TAMURA. Heterocycles 27:1249–1252

21.

Wada K, Bando H, Amiya T et al (1989) Studies on Aconitum species. XI. Two new diterpenoid alkaloids from Aconitum yesoense var. macroyesoense (NAKAI) TAMURA V. Heterocycles 29:2141–2148CrossRef

22.

Wada K, Bando H, Kawahara N (1990) Studies on Aconitum species. XIII. Two new diterpenoid alkaloids from Aconitum yesoense var. macroyesoense (NAKAI) TAMURA VI. Heterocycles 31:1081–1088

23.

Bando H, Kanaiwa Y, Wada K et al (1981) Structure of deoxyjesaconitine. A new diterpene alkaloid from Aconitum subcuneatum NAKAI. Heterocycles 16:1723–1725

24.

Mori T, Bando H, Kanaiwa Y et al (1983) Studies on the constituents of Aconitum Species. II. Structure of deoxyjesaconitine. Chem Pharm Bull 31:2884–2886

25.

Wada K, Bando H, Mori T et al (1985) Studies on the constituents of Aconitum Species. III. On the components of Aconitum subcuneatum NAKAI. Chem Pharm Bull 33:3658–3661

26.

Wada K, Bando H, Watanabe M et al (1985) Studies on the constituents of Aconitum Species. IV. On the components of Aconitum japonicum THUNB. Chem Pharm Bull 33:4717–4722

27.

Bando H, Wada K, Amiya T et al (1988) Studies on the constituents of Aconitum Species. VII. On the components of Aconitum japonicum THUNB. Heterocycles 27:2167–2174CrossRef

28.

Bando H, Wada K, Tanaka J et al (1989) Two new diterpenoid alkaloids from Delphinium pacific giant and revised ¹³C-NMR assignment of delpheline. Heterocycles 29:293–1300CrossRef

29.

Wada K, Yamamoto T, Bando H et al (1992) Four diterpenoid alkaloids from Delphinium elatum. Phytochemistry 31:2135–2138CrossRef

30.

Jalal Hosseinimehr S, Inanami O, Hamasu T et al (2004) Activation of C-Kit by stem cell factor induces radioresistance to apoptosis through ERK-dependent expression of survivin in HL60 cells. J Radiat Res 45:557–561PubMedCrossRef

31.

Liu Y, Nakahara T, Miyakoshi J et al (2007) Nuclear accumulation and activation of nuclear factor kB after split-dose irradiation in LS174T cells. J Radiat Res 48:13–20PubMedCrossRef

32.

Hall EJ (2000) Radiobiology for the radiologist. Lippincott, Philadelphia

33.

Chodoeva A, Bosc JJ, Guillon J et al (2005) 8-O-Azeloyl-benzoylaconine: a new alkaloid from the roots of Aconitum karacolicum Rapcss and its antiproliferative activities. Bioorg Med Chem 13:6493–6501PubMedCrossRef

34.

Kobayashi J (2004) Molecular mechanism of the recruitment of NBS1/hMRE11/hRAD50 complex to DNA double-strand breaks: NBS1 binds to g-H2AX through FHA/BRCT domain. J Radiat Res 45:473–478PubMedCrossRef

35.

Takahashi A, Ohnishi T (2005) Dose gH2AX foci formation depend on the presence of DNA double strand breaks? Cancer Lett 229:171–179PubMedCrossRef

Titel: Suppressive effects of novel derivatives prepared from Aconitum alkaloids on tumor growth
verfasst von: Masaharu Hazawa
Koji Wada
Kenji Takahashi
Takao Mori
Norio Kawahara
Ikuo Kashiwakura
Publikationsdatum: 01.04.2009
Verlag: Springer US
Erschienen in: Investigational New Drugs / Ausgabe 2/2009
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-008-9141-4

Neu im Fachgebiet Onkologie

Hodgkin Lymphom: BrECADD-Regime übertrifft die Erwartungen

05.06.2024 ASCO 2024 Kongressbericht

Das Kombinationsregime BrECADD mit Brentuximab vedotin ermöglichte in der Studie HD21 beim fortgeschrittenen klassischen Hodgkin-Lymphom eine unerwartet hohe progressionsfreie Überlebensrate von 94,3% nach vier Jahren. Gleichzeitig war das Regime besser tolerabel als der bisherige Standard eBEACOPP.

Antikörper-Drug-Konjugat verdoppelt PFS bei Multiplem Myelom

05.06.2024 ASCO 2024 Nachrichten

Zwei Phase-3-Studien deuten auf erhebliche Vorteile des Antikörper-Wirkstoff-Konjugats Belantamab-Mafodotin bei vorbehandelten Personen mit Multiplem Myelom: Im Vergleich mit einer Standard-Tripeltherapie wurde das progressionsfreie Überleben teilweise mehr als verdoppelt.

Neuer TKI gegen CML: Höhere Wirksamkeit, seltener Nebenwirkungen

05.06.2024 Chronische myeloische Leukämie Nachrichten

Der Tyrosinkinasehemmer (TKI) Asciminib ist älteren Vertretern dieser Gruppe bei CML offenbar überlegen: Personen mit frisch diagnostizierter CML entwickelten damit in einer Phase-3-Studie häufiger eine gut molekulare Response, aber seltener ernste Nebenwirkungen.

Brustkrebs-Prävention wird neu gedacht

04.06.2024 ASCO 2024 Kongressbericht

Zurzeit untersuchen Forschende verschiedene neue Ansätze zur Prävention von Brustkrebs bei Personen mit hohem Risiko. Darunter Denosumab, die prophylaktische Bestrahlung der Brust – und Impfungen.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Summary

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2009

Application of population pharmacokinetic modeling in early clinical development of the anticancer agent E7820

Trastuzumab induces gastrointestinal side effects in HER2-overexpressing breast cancer patients

Bowel perforation in non-small cell lung cancer after bevacizumab therapy

Synthesis and antiproliferative activity of substituted diazaspiro hydantoins: a structure–activity relationship study