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An orally active Amazonian plant extract (BIRM) inhibits prostate cancer growth and metastasis

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Abstract

Purpose

Poor efficacy of conventional chemotherapeutic drugs against metastatic hormone-refractory prostate cancer (CaP) drives patients to try "alternative medicine". The antitumor activity of one such agent, "BIRM" (biological immune response modulator; "Simple Ecuadorian Oral Solution: an extract of an Amazonian plant"), was characterized in vitro and in vivo using established CaP cell lines and a tumor model.

Methods

The cytotoxicity of BIRM in four human and one rat CaP cell line was evaluated using cell proliferation-inhibition and clonogenic survival assays. BIRM-induced apoptosis, alterations in cell cycle phase progression and inhibition of the extracellular matrix-degrading enzyme hyaluronidase were also investigated in these cells. The in vivo efficacy of BIRM was evaluated in rats with subcutaneous tumor implants of Dunning EGFP-MAT LyLu cells. The active species in BIRM were characterized by gel filtration chromatography.

Results

BIRM inhibited cell proliferation and clonogenic growth of the CaP cells (IC50 about 8.0 μl/ml). It increased cell accumulation in the G0/G1 phase by 33.8% and decreased the proportion of cells in S phase by 54.6%. Apoptotic cell death in BIRM-treated cells was associated with activation of cell death-associated caspases. BIRM inhibited the activity of hyaluronidase, a hyaluronic acid-degrading enzyme, at 1 μl/ml. Treatment of MAT LyLu tumor-bearing rats with BIRM by oral gavage resulted in a significant decrease in tumor incidence (50%), tumor growth rate (18.6±1.3 days for 1 cc tumor growth in control rats and 25.7±2.6 days in BIRM-treated rats), and only one out of six BIRM-treated rats versus four out of six in the control group developed lung metastasis. Three active ingredients in BIRM with a relative molecular mass (Mr) of ≥3500 were identified by ultracentrifugation and gel filtration chromatography and were found to be resistant to proteinase and heat (100°C).

Conclusion

The plant extract BIRM contains antitumor compounds of Mr ≥3500 with potent antiproliferative activity in vitro and in vivo against prostate cancer cells.

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Abbreviations

CaP:

Prostate cancer/cancer of the prostate

EGFP:

Enhanced green fluorescence protein

HA:

Hyaluronic acid

HAase:

Hyaluronidase

MTT:

Methyl thiozolyl tetrazolium bromide [(3-[4,5-demethylthiozol-2-y]-2,5-diphenyl tetrazolium bromide]

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Acknowledgements

The authors dedicate this work to Mr. Christian DeGetau von Forckenbeck (late) for introducing us to BIRM. The authors thank Rita Mourelatos, Monica Lopez and Dr. Tie Yan Shang for technical assistance and Dr. A. Krishan for the use of his flow cytometry facility.

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Authors and Affiliations

  1. Department of Urology, McKnight Vision Research Building, University of Miami School of Medicine, Miami, Florida, 33101, USA

    Devendra S. Dandekar, Vinata B. Lokeshwar, Mark S. Soloway & Balakrishna L. Lokeshwar

  2. Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida, 33101, USA

    Devendra S. Dandekar, Vinata B. Lokeshwar, Mark S. Soloway & Balakrishna L. Lokeshwar

  3. Instituto de Tumores, Quito, Ecuador

    Edwin Cevallos-Arellano

Authors
  1. Devendra S. Dandekar
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  2. Vinata B. Lokeshwar
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  3. Edwin Cevallos-Arellano
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  4. Mark S. Soloway
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  5. Balakrishna L. Lokeshwar
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Corresponding author

Correspondence to Balakrishna L. Lokeshwar.

Additional information

This work was supported in part by PHS grants R01 CA 61038 (B.L.L.), CA 72821 (V.B.L.), and DoD Grants DAMD 179818526 (B.L.L.) and DAMD 170210005 (V.B.L.).

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Dandekar, D.S., Lokeshwar, V.B., Cevallos-Arellano, E. et al. An orally active Amazonian plant extract (BIRM) inhibits prostate cancer growth and metastasis. Cancer Chemother Pharmacol 52, 59–66 (2003). https://doi.org/10.1007/s00280-003-0612-1

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  • DOI: https://doi.org/10.1007/s00280-003-0612-1

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