PUBLICATION
Pilot Study of Jadomycin B Pharmacokinetics and Anti-Tumoral Effects in Zebrafish Larvae and Mouse Breast Cancer Xenograft Models
- Authors
- McKeown, B.T., Relja, N.J., Hall, S.R., Gebremeskel, S., MacLeod, J.M., Veinotte, C., Bennett, L.G., Ohlund, L.B., Sleno, L., Jakeman, D.L., Berman, J.N., Johnston, B., Goralski, K.B.
- ID
- ZDB-PUB-220820-8
- Date
- 2022
- Source
- Canadian journal of physiology and pharmacology 100(11): 1065-1076 (Journal)
- Registered Authors
- Berman, Jason, Veinotte, Chansey
- Keywords
- none
- MeSH Terms
-
- Animals
- Breast Neoplasms*
- Female
- Heterografts
- Humans
- Mice
- Pilot Projects
- Zebrafish*
- PubMed
- 35985040 Full text @ Can. J. Physiol. Pharmacol.
Citation
McKeown, B.T., Relja, N.J., Hall, S.R., Gebremeskel, S., MacLeod, J.M., Veinotte, C., Bennett, L.G., Ohlund, L.B., Sleno, L., Jakeman, D.L., Berman, J.N., Johnston, B., Goralski, K.B. (2022) Pilot Study of Jadomycin B Pharmacokinetics and Anti-Tumoral Effects in Zebrafish Larvae and Mouse Breast Cancer Xenograft Models. Canadian journal of physiology and pharmacology. 100(11):1065-1076.
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 12h from day 6-15 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.
Errata / Notes
This article is corrected by ZDB-PUB-230228-39.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping