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Signaling and drug sensitivity

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Abstract

Even though alterations in receptor and nonreceptor kinases are involved in the development of human cancer, many cancer cell lines still retain their responsiveness to growth factors. We have investigated the hypothesis that cellular signaling events regulate the sensitivity of cancer cells to chemotherapeutic agents. In 2008 human ovarian carcinoma cells, activation of a number of different transduction pathways resulted in a 2 to 4-fold increase in the sensitivity to cisplatin. These signaling events include pathways activated by the epidermal growth factor (EGF) receptor, tumor necrosis factor α (TNFα) receptor, bombesin receptor, protein kinase A (PKA), and protein kinase C (PKC). Enhanced sensitivity to chemotherapeutic agents is presumed to be mediated by phosphorylation of critical target protein(s). β-tubulin has been identified as one such target for the protein kinase A signaling cascade. For other signal transduction pathways the key substrates that regulate drug sensitivity have not yet been identified. Recent work has shown that DNA damaging agents activate signaling cascades one of which involves the Src, Ras, and Raf proteins as intermediates and results in induction of a number of genes, including c-fos, c-jun, and the growth arrest and DNA damage??inducible (gadd) genes. This signaling cascade has been shown to involve activation of protein kinase C and to have a protective function. With the growing understanding of how signaling events relate to damage response and drug sensitivity, new and potentially useful strategies for modulating drug sensitivity are evolving.

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Abbreviations

EGF:

epidermal growth factor

TNFα:

tumor necrosis factor α

PKA:

protein kinase A

PKC:

protein kinase C

cAMP:

cyclic adenosine 3',5'-monophosphate, cisplatin, cis-diamminedichloroplatinum(II)

[3H]DEP:

[3H]dichloro(ethylenediamine)platinum(II)

IBMX:

3-isobutyl-1-methylxanthine

TPA:

12-O-tetradecanoylphorbol 13- acetate

GSH:

glutathione

IC50 :

dose level resulting in 50% inhibition of cell survival

LD50 :

dose level resulting in lethal toxicity in 50% of animals tested, gadd genes-growth arrest and DNA damage - inducible genes

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Authors and Affiliations

  1. Department of Medicine 0812 and the Cancer Center, University of California San Diego, 9500 Gilman Drive, 92093-0812, La Jolla, CA, USA

    Randolph D. Christen, Jeffrey A. Jones, Doreen K. Hom, Relef Kröning, Dennis P. Gately, Franz B. Thiebaut, Gerrit Los & Stephen B. Howell

  2. Department of Gynecologic Oncology, Jikei University School of Medicine, Tokyo, Japan

    Seiji Isonishi

  3. Department of Radiotherapy and Oncology, Helsinki University Central Hospital, Helsinki, Finland

    Antti P. Jekunen

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  1. Randolph D. Christen
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  2. Seiji Isonishi
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  3. Jeffrey A. Jones
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  4. Antti P. Jekunen
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  5. Doreen K. Hom
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  7. Dennis P. Gately
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  9. Gerrit Los
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  10. Stephen B. Howell
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Christen, R.D., Isonishi, S., Jones, J.A. et al. Signaling and drug sensitivity. Cancer Metast Rev 13, 175–189 (1994). https://doi.org/10.1007/BF00689635

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