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Vaticanol C, a novel resveratrol tetramer, reduces lymph node and lung metastases of mouse mammary carcinoma carrying p53 mutation

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Abstract

Purpose

The effects of vaticanol C (Vat-C), a novel resveratrol tetramer, were studied in a mouse metastatic mammary cancer model carrying mutations in p53 that produce a metastatic spectrum similar to that seen in human breast cancers.

Methods

Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879 cells, were subsequently treated with Vat-C at 0, 100 and 200 ppm in their diet.

Results

The in vitro study demonstrated that Vat-C induced apoptosis, as inferred by morphological changes, nucleosomal DNA fragmentation and elevated activities of caspases. Although tumor volumes were not apparently suppressed in mice treated with Vat-C, the multiplicity of lymph node metastasis was significantly decreased in the 200-ppm group. Furthermore, the multiplicity of lung metastasis was also significantly lower in the 200-ppm group. In any category of organ metastasis, the number of organs with metastasis tended to be lower in the 200-ppm group, but these findings were not statistically significant. The levels of apoptosis were significantly higher in the 200-ppm group, but DNA synthesis only a tended to be lower in this group. Microvessel density in tumors also tended to be lower in the Vat-C-treated groups. Moreover, the numbers of lymphatic vessels having intraluminal tumor cells was significantly lower in mammary tumors of mice given 100 and 200-ppm Vat-C, indicating a reduction in migrating tumor cells into the lymphatic vessels of tumor tissue.

Conclusions

These results suggest that the observed antimetastatic activity of Vat-C may be of clinical significance as an adjuvant therapy in metastatic human breast cancer having p53 mutations, and may also be useful as a chemopreventative of breast cancer development.

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Abbreviations

BrdU:

5′-Bromo-2′-deoxyuridine

HUVEC:

Human umbilical vein endothelial cells

MMTV:

Mouse mammary tumor virus

PBS:

Phosphate-buffered saline

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP-FITC nick end-labeling

Vat-C:

Vaticanol C

vWF:

von Willebrand factor

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Acknowledgments

We thank the staff of the Central Research Laboratory and the Laboratory Animal Center, Osaka Medical College. We are also grateful to Ms. Hidemi Hiyama for warm-hearted secretarial assistance.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Division of Basic Medicine I, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka, 569-8686, Japan

    Masa-Aki Shibata & Yoshinori Otsuki

  2. Hi-Tech Research Center, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka, 569-8686, Japan

    Masa-Aki Shibata, Eiko Shibata & Yoshinori Otsuki

  3. Laboratory Animal Center, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka, 569-8686, Japan

    Junji Morimoto

  4. Gifu International Institute of Biotechnology, Kakamigahara, Gifu, 504-0838, Japan

    Yukihiro Akao & Yoshinori Nozawa

  5. Gifu Pharmaceutical University, Mitahora-higashi 5-6-1, Gifu, 502-8585, Japan

    Tetsuro Ito

  6. Nagaragawa Research Center, API Co. Ltd., 692-3 Nagara, Gifu, 502-0071, Japan

    Satoshi Mishima

Authors
  1. Masa-Aki Shibata
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  2. Yukihiro Akao
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  3. Eiko Shibata
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  4. Yoshinori Nozawa
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  5. Tetsuro Ito
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  6. Satoshi Mishima
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  7. Junji Morimoto
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  8. Yoshinori Otsuki
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Corresponding author

Correspondence to Masa-Aki Shibata.

Additional information

Grant support: This investigation was supported, in part, by a High-Tech Research Center Grant to Osaka Medical College from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Shibata, MA., Akao, Y., Shibata, E. et al. Vaticanol C, a novel resveratrol tetramer, reduces lymph node and lung metastases of mouse mammary carcinoma carrying p53 mutation. Cancer Chemother Pharmacol 60, 681–691 (2007). https://doi.org/10.1007/s00280-007-0414-y

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  • DOI: https://doi.org/10.1007/s00280-007-0414-y

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