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

Brendan T. McKeown; Nicholas J. Relja; Steven R. Hall; Simon Gebremeskel; Jeanna M. Macleod; Chansey J. Veinotte; Leah G. Bennett; Leanne B. Ohlund; Lekha Sleno; David L. Jakeman; Jason N. Berman; Brent Johnston; Kerry B. Goralski

doi:10.1139/cjpp-2022-0152

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

Brendan T. McKeown, Nicholas J. Relja, Steven R. Hall, Simon Gebremeskel, Jeanna M. Macleod, Chansey J. Veinotte, Leah G. Bennett, Leanne B. Ohlund, Lekha Sleno, David L. Jakeman, Jason N. Berman, Brent Johnston, Kerry B. Goralski

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

5 Citas (Scopus)

Resumen

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 con-trol. 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.

Idioma original	English
Páginas (desde-hasta)	1065-1076
Número de páginas	12
Publicación	Canadian Journal of Physiology and Pharmacology
Volumen	100
N.º	11
DOI	https://doi.org/10.1139/cjpp-2022-0152
Estado	Published - 2022

Nota bibliográfica

Funding Information:
This work was supported by operating grants from the Dalhousie Pharmacy Endowment, the Beatrice Hunter Cancer Research Institute, and the Canadian Breast Cancer Foundation —Atlantic Region (The Canadian Cancer Society). BTM was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Terry Fox Research Institute and with funds from the Natural Sciences and Engineering Research Council of Canada (CREATE Grant No. 510 963). NJR was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by a CIBC Graduate Scholarship in Medical Research and the Canadian Breast Cancer Foundation —Atlantic Region. SRH was supported by a trainee award from the Beatrice Hunter Cancer Research Institute with funds provided by Cancer Care Nova Scotia as part of the Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at CIHR, a Canadian Imperial Bank of Commerce Graduate Scholarship in Medical Research, a Nova Scotia Health Research Foundation Scotia Scholar Award, and a Level 2 Izaak Walton Killam Predoctoral Scholarship. SG received studentships from the Canadian Institutes of Health Research, Beatrice Hunter Cancer Research Institute, and Izaak Walton Killam Predoctoral Scholarship. JMM was supported through a graduate scholarship from the Canadian Institute of Health Research and through the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Terry Fox Research Institute and the Dalhousie Medical Research Foundation Gordon Stirrett Wealth Management Graduate Traineeship Award. LGB was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by a CIBC Graduate Scholarship in Medical Research and the QE2 Foundation. LS acknowledges funding from the Canadian Foundation for Innovation Leader’s Fund, a strategic chair in bioanalytical chemistry from UQAM, and mass spectrometry platform support from CERMO-FC (Centre d’Excellence de Recherche sur les Maladies Orphelines —Fondation Courtois).

Funding Information:
This work was supported by operating grants from the Dalhousie Pharmacy Endowment, the Beatrice Hunter Cancer Research Institute, and the Canadian Breast Cancer Foundation —Atlantic Region (The Canadian Cancer Society). BTM was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Terry Fox Research Institute and with funds from the Natural Sciences and Engineering Research Council of Canada (CREATE Grant No. 510 963). NJR was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by a CIBC Graduate Scholarship in Medical Research and the Canadian Breast Cancer Foundation —Atlantic Region. SRH was supported by a trainee award from the Beatrice Hunter Cancer Research Institute with funds provided by Cancer Care Nova Scotia as part of the Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at CIHR, a Canadian Imperial Bank of Commerce Graduate Scholarship in Medical Research, a Nova Scotia Health Research Foundation Scotia Scholar Award, and a Level 2 Izaak Walton Killam Predoctoral Scholarship. SG received studentships from the Canadian Institutes of Health Research, Beatrice Hunter Cancer Research Institute, and Izaak Walton Killam Predoctoral Scholarship. JMM was supported through a graduate scholarship from the Canadian Institute of Health Research and through the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Terry Fox Research Institute and the Dalhousie Medical Research Foundation Gordon Stirrett Wealth Management Graduate Traineeship Award. LGB was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by a CIBC Graduate Scholarship in Medical Research and the QE2 Foundation. LS acknowledges funding from the Canadian Foundation for Innovation Leader’s Fund, a strategic chair in bioanalytical chemistry from UQAM, and mass spectrometry platform sup-port from CERMO-FC (Centre d’Excellence de Recherche sur les Maladies Orphelines——Fondation Courtois).

Publisher Copyright:
© 2022 The Author(s).

ASJC Scopus Subject Areas

Physiology
Pharmacology
Physiology (medical)

PubMed: MeSH publication types

Journal Article

ODS de las Naciones Unidas

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10.1139/cjpp-2022-0152

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McKeown, B. T., Relja, N. J., Hall, S. R., Gebremeskel, S., Macleod, J. M., Veinotte, C. J., 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. https://doi.org/10.1139/cjpp-2022-0152

Pilot study of jadomycin B pharmacokinetics and anti-tumoral effects in zebrafish larvae and mouse breast cancer xenograft models. / McKeown, Brendan T.; Relja, Nicholas J.; Hall, Steven R. et al.
En: Canadian Journal of Physiology and Pharmacology, Vol. 100, N.º 11, 2022, p. 1065-1076.

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

McKeown, BT, Relja, NJ, Hall, SR, Gebremeskel, S, Macleod, JM, Veinotte, CJ, Bennett, LG, Ohlund, LB, Sleno, L, Jakeman, DL, Berman, JN, Johnston, B & Goralski, KB 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, vol. 100, n.º 11, pp. 1065-1076. https://doi.org/10.1139/cjpp-2022-0152

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

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 con-trol. 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.",

author = "McKeown, {Brendan T.} and Relja, {Nicholas J.} and Hall, {Steven R.} and Simon Gebremeskel and Macleod, {Jeanna M.} and Veinotte, {Chansey J.} and Bennett, {Leah G.} and Ohlund, {Leanne B.} and Lekha Sleno and Jakeman, {David L.} and Berman, {Jason N.} and Brent Johnston and Goralski, {Kerry B.}",

note = "Funding Information: This work was supported by operating grants from the Dalhousie Pharmacy Endowment, the Beatrice Hunter Cancer Research Institute, and the Canadian Breast Cancer Foundation —Atlantic Region (The Canadian Cancer Society). BTM was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Terry Fox Research Institute and with funds from the Natural Sciences and Engineering Research Council of Canada (CREATE Grant No. 510 963). NJR was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by a CIBC Graduate Scholarship in Medical Research and the Canadian Breast Cancer Foundation —Atlantic Region. SRH was supported by a trainee award from the Beatrice Hunter Cancer Research Institute with funds provided by Cancer Care Nova Scotia as part of the Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at CIHR, a Canadian Imperial Bank of Commerce Graduate Scholarship in Medical Research, a Nova Scotia Health Research Foundation Scotia Scholar Award, and a Level 2 Izaak Walton Killam Predoctoral Scholarship. SG received studentships from the Canadian Institutes of Health Research, Beatrice Hunter Cancer Research Institute, and Izaak Walton Killam Predoctoral Scholarship. JMM was supported through a graduate scholarship from the Canadian Institute of Health Research and through the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Terry Fox Research Institute and the Dalhousie Medical Research Foundation Gordon Stirrett Wealth Management Graduate Traineeship Award. LGB was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by a CIBC Graduate Scholarship in Medical Research and the QE2 Foundation. LS acknowledges funding from the Canadian Foundation for Innovation Leader{\textquoteright}s Fund, a strategic chair in bioanalytical chemistry from UQAM, and mass spectrometry platform support from CERMO-FC (Centre d{\textquoteright}Excellence de Recherche sur les Maladies Orphelines —Fondation Courtois). Funding Information: This work was supported by operating grants from the Dalhousie Pharmacy Endowment, the Beatrice Hunter Cancer Research Institute, and the Canadian Breast Cancer Foundation —Atlantic Region (The Canadian Cancer Society). BTM was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Terry Fox Research Institute and with funds from the Natural Sciences and Engineering Research Council of Canada (CREATE Grant No. 510 963). NJR was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by a CIBC Graduate Scholarship in Medical Research and the Canadian Breast Cancer Foundation —Atlantic Region. SRH was supported by a trainee award from the Beatrice Hunter Cancer Research Institute with funds provided by Cancer Care Nova Scotia as part of the Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at CIHR, a Canadian Imperial Bank of Commerce Graduate Scholarship in Medical Research, a Nova Scotia Health Research Foundation Scotia Scholar Award, and a Level 2 Izaak Walton Killam Predoctoral Scholarship. SG received studentships from the Canadian Institutes of Health Research, Beatrice Hunter Cancer Research Institute, and Izaak Walton Killam Predoctoral Scholarship. JMM was supported through a graduate scholarship from the Canadian Institute of Health Research and through the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Terry Fox Research Institute and the Dalhousie Medical Research Foundation Gordon Stirrett Wealth Management Graduate Traineeship Award. LGB was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by a CIBC Graduate Scholarship in Medical Research and the QE2 Foundation. LS acknowledges funding from the Canadian Foundation for Innovation Leader{\textquoteright}s Fund, a strategic chair in bioanalytical chemistry from UQAM, and mass spectrometry platform sup-port from CERMO-FC (Centre d{\textquoteright}Excellence de Recherche sur les Maladies Orphelines——Fondation Courtois). Publisher Copyright: {\textcopyright} 2022 The Author(s).",

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doi = "10.1139/cjpp-2022-0152",

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T1 - Pilot study of jadomycin B pharmacokinetics and anti-tumoral effects in zebrafish larvae and mouse breast cancer xenograft models

AU - McKeown, Brendan T.

AU - Relja, Nicholas J.

AU - Hall, Steven R.

AU - Gebremeskel, Simon

AU - Macleod, Jeanna M.

AU - Veinotte, Chansey J.

AU - Bennett, Leah G.

AU - Ohlund, Leanne B.

AU - Sleno, Lekha

AU - Jakeman, David L.

AU - Berman, Jason N.

AU - Johnston, Brent

AU - Goralski, Kerry B.

N1 - Funding Information: This work was supported by operating grants from the Dalhousie Pharmacy Endowment, the Beatrice Hunter Cancer Research Institute, and the Canadian Breast Cancer Foundation —Atlantic Region (The Canadian Cancer Society). BTM was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Terry Fox Research Institute and with funds from the Natural Sciences and Engineering Research Council of Canada (CREATE Grant No. 510 963). NJR was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by a CIBC Graduate Scholarship in Medical Research and the Canadian Breast Cancer Foundation —Atlantic Region. SRH was supported by a trainee award from the Beatrice Hunter Cancer Research Institute with funds provided by Cancer Care Nova Scotia as part of the Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at CIHR, a Canadian Imperial Bank of Commerce Graduate Scholarship in Medical Research, a Nova Scotia Health Research Foundation Scotia Scholar Award, and a Level 2 Izaak Walton Killam Predoctoral Scholarship. SG received studentships from the Canadian Institutes of Health Research, Beatrice Hunter Cancer Research Institute, and Izaak Walton Killam Predoctoral Scholarship. JMM was supported through a graduate scholarship from the Canadian Institute of Health Research and through the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Terry Fox Research Institute and the Dalhousie Medical Research Foundation Gordon Stirrett Wealth Management Graduate Traineeship Award. LGB was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by a CIBC Graduate Scholarship in Medical Research and the QE2 Foundation. LS acknowledges funding from the Canadian Foundation for Innovation Leader’s Fund, a strategic chair in bioanalytical chemistry from UQAM, and mass spectrometry platform support from CERMO-FC (Centre d’Excellence de Recherche sur les Maladies Orphelines —Fondation Courtois). Funding Information: This work was supported by operating grants from the Dalhousie Pharmacy Endowment, the Beatrice Hunter Cancer Research Institute, and the Canadian Breast Cancer Foundation —Atlantic Region (The Canadian Cancer Society). BTM was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Terry Fox Research Institute and with funds from the Natural Sciences and Engineering Research Council of Canada (CREATE Grant No. 510 963). NJR was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by a CIBC Graduate Scholarship in Medical Research and the Canadian Breast Cancer Foundation —Atlantic Region. SRH was supported by a trainee award from the Beatrice Hunter Cancer Research Institute with funds provided by Cancer Care Nova Scotia as part of the Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at CIHR, a Canadian Imperial Bank of Commerce Graduate Scholarship in Medical Research, a Nova Scotia Health Research Foundation Scotia Scholar Award, and a Level 2 Izaak Walton Killam Predoctoral Scholarship. SG received studentships from the Canadian Institutes of Health Research, Beatrice Hunter Cancer Research Institute, and Izaak Walton Killam Predoctoral Scholarship. JMM was supported through a graduate scholarship from the Canadian Institute of Health Research and through the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Terry Fox Research Institute and the Dalhousie Medical Research Foundation Gordon Stirrett Wealth Management Graduate Traineeship Award. LGB was a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by a CIBC Graduate Scholarship in Medical Research and the QE2 Foundation. LS acknowledges funding from the Canadian Foundation for Innovation Leader’s Fund, a strategic chair in bioanalytical chemistry from UQAM, and mass spectrometry platform sup-port from CERMO-FC (Centre d’Excellence de Recherche sur les Maladies Orphelines——Fondation Courtois). Publisher Copyright: © 2022 The Author(s).

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Y1 - 2022

N2 - 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 con-trol. 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.

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

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