Differential effects of bryostatins and phorbol esters on arachidonic acid metabolite release and epidermal growth factor binding in C3H 10T 1/2 cells

M. L. Dell'Aquila, C. L. Herald, Y. Kamano, George Pettit, P. M. Blumberg

Research output: Contribution to journalArticle

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Abstract

The bryostatins, a group of macrocyclic lactones isolated on the basis of their antineoplastic activity, activate protein kinase C in vitro and block phorbol ester binding to this enzyme. In some cellular systems, bryostatins mimic phorbol ester action. In other systems, however, the bryostatins display only marginal agonistic action and, instead, inhibit phorbol ester-induced responses. At least in primary mouse epidermal cells, a transient duration of action of bryostatin 1 could rationalize these differences. To determine whether this model of transient activation could explain the dual actions of bryostatin 1 in other cell systems, we have examined the effects of bryostatin 1 on short-term responses in C3H 10T 1/2 mouse fibroblasts. Even at very short exposures (30 min), bryostatin 1 blocked phorbol ester-induced arachidonic acid metabolite release and induced only minimal release when assayed alone. In contrast, epidermal growth factor binding was markedly and rapidly decreased in bryostatin 1-treated C3H 10T 1/2 cells, and this disease showed only limited reversal 16 h after initial exposure. Bryostatins 2, 3, 4, 10, and several of their derivatives caused variable arachidonic acid metabolite release (10 to 60% of phorbol ester control) and correspondingly variable inhibition of phorbol ester action. Our findings on arachidonic acid metabolite release argue against transient activation of the protein kinase C pathway as the sole explanation of bryostatin 1 action. They indicate, moreover, differences in the structure-activity relations of the bryostatins for the phorbol ester-mimetic and phorbol ester-inhibitory actions.

Original languageEnglish (US)
Pages (from-to)3702-3708
Number of pages7
JournalCancer Research
Volume48
Issue number13
StatePublished - 1988
Externally publishedYes

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Bryostatins
Phorbol Esters
Epidermal Growth Factor
Arachidonic Acid
Protein Kinase C
Lactones
Antineoplastic Agents
bryostatin 1
Fibroblasts

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Differential effects of bryostatins and phorbol esters on arachidonic acid metabolite release and epidermal growth factor binding in C3H 10T 1/2 cells. / Dell'Aquila, M. L.; Herald, C. L.; Kamano, Y.; Pettit, George; Blumberg, P. M.

In: Cancer Research, Vol. 48, No. 13, 1988, p. 3702-3708.

Research output: Contribution to journalArticle

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abstract = "The bryostatins, a group of macrocyclic lactones isolated on the basis of their antineoplastic activity, activate protein kinase C in vitro and block phorbol ester binding to this enzyme. In some cellular systems, bryostatins mimic phorbol ester action. In other systems, however, the bryostatins display only marginal agonistic action and, instead, inhibit phorbol ester-induced responses. At least in primary mouse epidermal cells, a transient duration of action of bryostatin 1 could rationalize these differences. To determine whether this model of transient activation could explain the dual actions of bryostatin 1 in other cell systems, we have examined the effects of bryostatin 1 on short-term responses in C3H 10T 1/2 mouse fibroblasts. Even at very short exposures (30 min), bryostatin 1 blocked phorbol ester-induced arachidonic acid metabolite release and induced only minimal release when assayed alone. In contrast, epidermal growth factor binding was markedly and rapidly decreased in bryostatin 1-treated C3H 10T 1/2 cells, and this disease showed only limited reversal 16 h after initial exposure. Bryostatins 2, 3, 4, 10, and several of their derivatives caused variable arachidonic acid metabolite release (10 to 60{\%} of phorbol ester control) and correspondingly variable inhibition of phorbol ester action. Our findings on arachidonic acid metabolite release argue against transient activation of the protein kinase C pathway as the sole explanation of bryostatin 1 action. They indicate, moreover, differences in the structure-activity relations of the bryostatins for the phorbol ester-mimetic and phorbol ester-inhibitory actions.",
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