Involvement of PKC βII in anti‐proliferating action of a new antitumor compound gnidimacrin

• Published in: International journal of cancer Vol. 105; no. 5; pp. 601 - 606
• Main Authors: Yoshida, Mitsuzi, Heike, Yuji, Ohno, Shigeo, Ikekawa, Tetsuro, Wakasugi, Hiro
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 10.07.2003; Wiley-Liss
• Subjects: Biological and medical sciences; bryostatin 1; downregulation; gene transfection; General pharmacology; gnidimacrin; Medical sciences; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; PKC; Antineoplastic agent; Human; Lung disease; Protein kinase C; Respiratory disease; Enzyme; Pharmacognosy; Isozyme; Transferases; Leukemia; Malignant hemopathy; Malignant tumor; In vitro; Biological activity; Bronchopulmonary; HL60 cell line; Established cell line; Plant origin; Bronchus disease; Small cell carcinoma
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.11157

Daphnane‐type diterpene gnidimacrin (NSC 252940) shows significant antitumor activity against murine tumors and human tumor cell lines. This compound binds to and directly activates protein kinase C (PKC), arresting the cell cycle at the G1 phase through inhibition of cdk2 activity in human K562 leukemia cells. In our study, we examined whether cellular PKC is involved in the antiproliferating effect of gnidimacrin. In a 24‐hr exposure of K562 cells to high concentrations of bryostatin 1 (0.11–3.3 μM), both expression of PKC α and PKC βII was downregulated, and thereafter these cells became resistant to gnidimacrin in response to the degree of PKC downregulation. In addition, PKC α and PKC βII genes were transfected to gnidimacrin‐resistant human hepatoma HLE cells that demonstrated positive expression of PKC α and negative expression of PKC βII. PKC βII gene‐transfected cells became sensitive to gnidimacrin in relation to the degree of PKC βII expression. The most sensitive clone to show 0.001 μg/mL (1.2 nM) as IC50 in a continuous 4‐day exposure was obtained. While PKC α gene‐transfected cells exhibited an increase in PKC α expression and became sensitive to gnidimacrin, sensitivity was one‐hundredth of that in PKC βII gene‐transfected cells. These results suggest that PKC, in particular PKC βII, is necessary in the antitumor effect of gnidimacrin. © 2003 Wiley‐Liss, Inc.