Pilot study of jadomycin B pharmacokinetics and anti-tumoral effects in zebrafish larvae and mouse breast cancer xenograft models

  • Can J Physiol Pharmacol. 2022 Nov 1;100(11):1065-1076. doi: 10.1139/cjpp-2022-0152.
Brendan T McKeown  1  2 ,  Nicholas J Relja  3 ,  Steven R Hall  1 ,  Simon Gebremeskel  4 ,  Jeanna M MacLeod  3 ,  Chansey J Veinotte  5 ,  Leah G Bennett  3 ,  Leanne B Ohlund  6 ,  Lekha Sleno  6 ,  David L Jakeman  3  7 ,  Jason N Berman  5  8  9 ,  Brent Johnston  2  4  10 ,  Kerry B Goralski  1  2  3  5
Affiliations
  • 1. Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, B3H 4R2, Canada.
  • 2. Beatrice Hunter Cancer Research Institute, Halifax, NS, B3H 4R2, Canada.
  • 3. Faculty of Health, College of Pharmacy, Dalhousie University, Halifax, NS, B3H 4R2, Canada.
  • 4. Department of Microbiology & Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS, B3H 4R2, Canada.
  • 5. Division of Pediatric Hematology/Oncology, Department of Pediatrics, IWK Health Centre, Halifax, NS, B3K 6R8, Canada.
  • 6. Chemistry department/CERMO-FC, Faculty of Sciences, Université du Québec à Montréal, Montréal, QC, H2X 2J6, Canada.
  • 7. Department of Chemistry, Faculty of Science, Dalhousie University, Halifax, NS, B3H 4R2, Canada.
  • 8. Children's Hospital of Eastern Ontario Research Institute and Department of Pediatrics, University of Ottawa, Ottawa, ON, K1H 5B2, Canada.
  • 9. Department of Pediatrics, Faculty of Medicine, Dalhousie University, Halifax, NS, B3H 4R2, Canada.
  • 10. Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS, B3H 4R2, Canada.
PMID: 35985040 DOI: 10.1139/cjpp-2022-0152
Abstract

Despite numerous therapeutic options, multidrug resistance (MDR) remains an obstacle to successful breast Cancer therapy. Jadomycin B, a natural product derived from Streptomyces venezuelae ISP5230, maintains cytotoxicity in MDR human breast Cancer cells. Our objectives were to evaluate the pharmacokinetics, toxicity, anti-tumoral, and anti-metastatic effects of jadomycin B in zebrafish larvae and mice. In a zebrafish larval xenograft model, jadomycin B significantly reduced the proliferation of human MDA-MB-231 cells at or below its maximum tolerated dose (40 µm). In female Balb/C mice, a single intraperitoneal dose (6 mg/kg) was rapidly absorbed with a maximum serum concentration of 3.4 ± 0.27 µm. Jadomycin B concentrations declined biphasically with an elimination half-life of 1.7 ± 0.058 h. In the 4T1 mouse mammary carcinoma model, jadomycin B (12 mg/kg every 12 h from day 6 to 15 after tumor cell injection) decreased primary tumor volume compared to vehicle control. Jadomycin B-treated mice did not exhibit weight loss, nor significant increases in biomarkers of impaired hepatic (alanine aminotransferase) and renal (creatinine) function. In conclusion, jadomycin B demonstrated a good safety profile and provided partial anti-tumoral effects, warranting further dose-escalation safety and efficacy studies in MDR breast Cancer models.

Keywords
breast cancer; cancer du sein; jadomycin B; jadomycine B; mouse; pharmacocinétique; pharmacokinetics; poisson-zèbre; souris; toxicity; toxicité; zebrafish.
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