Phorbol esters induce multidrug resistance in human breast cancer cells

Journal Article · Fri Jan 01 04:00:00 EST 1988 · Proc. Natl. Acad. Sci. U.S.A.; (United States)

DOI:https://doi.org/10.1073/pnas.85.2.582· OSTI ID:6201516

Fine, R L; Patel, J; Chabner, B A

Mechanisms responsible for broad-based resistance to antitumor drugs derived from natural products (multidrug resistance) are incompletely understood. Agents known to reverse the multidrug-resistant phenotype (verapamil and trifluoperazine) can also inhibit the activity of protein kinase C. When the authors assayed human breast cancer cell lines for protein kinase C activity, they found that enzyme activity was 7-fold higher in the multidrug-resistance cancer cells compared with the control, sensitive parent cells. Exposure of drug-sensitive cells to the phorbol ester phorbol 12,13-dibutyate (P(BtO)/sub 2/) led to an increase in protein kinase C activity and induced a drug-resistance phenotype, whereas exposure of drug-resistant cells to P(BtO)/sub 2/ further increased drug resistance. In sensitive cells, this increased resistance was accomplished by a 3.5-fold increased phosphorylation of a 20-kDa particulate protein and a 35-40% decreased intracellular accumulation of doxorubicin and vincristine. P(BtO)/sub 2/ induced resistance to agents involved in the multidrug-resistant phenotype (doxorubicin and vincristine) but did not affect sensitivity to an unrelated alkylating agent (melphalan). The increased resistance was partially or fully reversible by the calcium channel blocker verapamil and by the calmodulin-antagonist trifluoperazine. These data suggest that stimulation of protein kinase C playus a role in the drug-transport changes in multidrug-resistant cells. This may occur through modulation of an efflux pump by protein phosphorylation.

• Research Organization: National Institute of Mental Health, Bethesda, MD (USA)
• OSTI ID: 6201516
• Journal Information: Proc. Natl. Acad. Sci. U.S.A.; (United States), Journal Name: Proc. Natl. Acad. Sci. U.S.A.; (United States) Vol. 85:2; ISSN PNASA
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALKALOIDS
ANIMAL CELLS
ANIMALS
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
ANTINEOPLASTIC DRUGS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOLOGICAL EFFECTS
BODY
CARBON 14 COMPOUNDS
CARCINOGENS
CARCINOMAS
CHEMOTHERAPY
DAYS LIVING RADIOISOTOPES
DISEASES
DOXORUBICIN
DRUGS
ENZYMES
ESTERS
GLANDS
ISOTOPES
LABELLED COMPOUNDS
LIGHT NUCLEI
MAMMALS
MAMMARY GLANDS
MAN
MEMBRANE TRANSPORT
METABOLISM
NEOPLASMS
NUCLEI
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
ORGANS
PHORBOL ESTERS
PHOSPHORUS 32
PHOSPHORUS ISOTOPES
PHOSPHORUS-GROUP TRANSFERASES
PHOSPHOTRANSFERASES
PRIMATES
RADIOISOTOPES
SENSITIVITY
THERAPY
TRANSFERASES
TRITIUM COMPOUNDS
TUMOR CELLS
VERTEBRATES