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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Antiproliferative effect in vitro and antitumor activity in vivo of brefeldin A
E A Sausville1, K L Duncan, A Senderowicz
1Laboratory of Biological Chemistry, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892-7458, USA.
Purpose:
An empiric in vitro screen of human tumor cell lines found brefeldin A inhibited the growth of immortalized human cell lines, with particular sensitivity to brefeldin in a series of immortalized melanoma cell lines and nonimmortalized prostate carcinoma explants. Brefeldin A alters the morphology and function of the Golgi apparatus, endosomal, and trans-Golgi compartments in different cell types. The studies presented here sought to obtain evidence of in vivo antitumor activity by brefeldin A.
Methods:
Antiproliferative activity was studied in prostate carcinoma cells in vitro using cell counts, protein, and viable stains. Activity was also studied in vivo against subcutaneous and subrenal capsule melanoma models.
Results:
Protracted exposures in vitro (between 24 and 72 hours) are necessary to cause persistent growth inhibition of immortalized PC3 prostate carcinoma cells. In human melanoma athymic mouse xenografts, brefeldin A showed antitumor activity in vivo when given 16 to 64 mg/kg/injection intraperitoneally q 7 h x 2, daily for 5 days. Activity was also observed in the intraperitoneal LOX IMVI (65%-100% increase in life span, with 17%-50% day 60 survivors); early-stage subcutaneous LOX IMVI and SK-MEL-5 (86%-100% growth inhibition), and subrenal capsule SK-MEL-5 and M19-MEL models.
Conclusions:
Brefeldin A possesses noteworthy antitumor activity in vivo and antiproliferative effects in vitro in certain cell types. Strategies to allow protracted exposure of tumor cells to brefeldin A while preserving a therapeutic index are needed to assess the clinical potential of brefeldin A.
Insights
Brefeldin A demonstrates significant antitumor effects in vivo and antiproliferative activity against specific cancer cells in vitro. Further research is needed to optimize its clinical application by ensuring prolonged tumor cell exposure.
Area of Science:
- Pharmacology
- Cancer Biology
- Cell Biology
Background:
- Brefeldin A is known to affect Golgi apparatus, endosomal, and trans-Golgi compartments.
- Previous in vitro studies indicated brefeldin A's inhibitory effect on immortalized human cell lines, particularly melanoma and prostate carcinoma cells.
Purpose of the Study:
- To investigate the in vivo antitumor activity of brefeldin A.
- To evaluate the antiproliferative effects of brefeldin A in specific cancer models.
Main Methods:
- In vitro antiproliferative activity was assessed in prostate carcinoma cells using cell counts and viability stains.
- In vivo antitumor activity was evaluated in athymic mouse xenograft models of melanoma and prostate carcinoma.
Main Results:
- Protracted in vitro exposure (24-72 hours) was required for persistent growth inhibition of PC3 prostate carcinoma cells.
- Brefeldin A exhibited in vivo antitumor activity in human melanoma xenografts, increasing lifespan and survival rates in various models.
- Significant growth inhibition was observed in subcutaneous and subrenal capsule melanoma models.
Conclusions:
- Brefeldin A shows notable in vivo antitumor activity and in vitro antiproliferative effects in specific cell types.
- Developing strategies for sustained tumor cell exposure to brefeldin A is crucial for assessing its clinical potential.
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