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The effect of doxorubicin on MEK-ERK signaling predicts its efficacy in HCC.
J Surg Res. 2008 Dec; 150(2):219-26.JS

Abstract

BACKGROUND

Hepatocellular cancer (HCC) is a leading cause of cancer-related death worldwide. Historically, doxorubicin (DOX) has been widely used against unresectable HCC with variable response rates.

MATERIALS AND METHODS

We hypothesized that DOX combined with mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (MEK-ERK) targeted therapy may provide enhanced anti-cancer effects. Human HCC cell lines (HepG2, Hep3B) were treated with DOX and MEK enzyme inhibitors, U0126 or PD184161, alone or in combination. Growth, apoptosis, and ERK expression/MEK activity were respectively determined by proliferation assay, DNA fragmentation enzyme-linked immunoassay or fluorochrome inhibitor of caspases, and Western blot.

RESULTS

DOX (0.01-1 microM) decreased cell proliferation in Hep3B cells (IC(50) approximately 0.12 microM) at 48 to 72 h; DOX was less effective in HepG2 cells (IC(50) approximately 0.25 microM). At early time points (30 min) after DOX treatment of Hep3B cells, MEK activity was unchanged at low doses and decreased at higher doses; after 24 h, phospho-ERK levels increased at higher doses. Contrarily, in HepG2 cells, DOX caused a sustained, dose-dependent increase in phospho-ERK levels at early and late time points. The MEK inhibitor U0126 decreased phospho-ERK in both HCC lines. In contrast to DOX, HepG2 cells were more sensitive than Hep3B cells to U0126. The combination of DOX with U0126 (or PD184161) resulted in greater inhibition of proliferation in HepG2 but not in Hep3B cells. This effect may be mediated in part by enhanced apoptosis.

CONCLUSIONS

The effect of DOX on early and late induction of MEK activity predicts its chemotherapeutic response in HCC. Furthermore, this effect may also determine the utility of MEK inhibitor combination treatment.

Authors+Show Affiliations

Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18468633

Citation

Choi, Jennifer, et al. "The Effect of Doxorubicin On MEK-ERK Signaling Predicts Its Efficacy in HCC." The Journal of Surgical Research, vol. 150, no. 2, 2008, pp. 219-26.
Choi J, Yip-Schneider M, Albertin F, et al. The effect of doxorubicin on MEK-ERK signaling predicts its efficacy in HCC. J Surg Res. 2008;150(2):219-26.
Choi, J., Yip-Schneider, M., Albertin, F., Wiesenauer, C., Wang, Y., & Schmidt, C. M. (2008). The effect of doxorubicin on MEK-ERK signaling predicts its efficacy in HCC. The Journal of Surgical Research, 150(2), 219-26. https://doi.org/10.1016/j.jss.2008.01.029
Choi J, et al. The Effect of Doxorubicin On MEK-ERK Signaling Predicts Its Efficacy in HCC. J Surg Res. 2008;150(2):219-26. PubMed PMID: 18468633.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effect of doxorubicin on MEK-ERK signaling predicts its efficacy in HCC. AU - Choi,Jennifer, AU - Yip-Schneider,Michele, AU - Albertin,Faith, AU - Wiesenauer,Chad, AU - Wang,Yufang, AU - Schmidt,C Max, Y1 - 2008/03/03/ PY - 2007/09/05/received PY - 2007/12/11/revised PY - 2008/01/16/accepted PY - 2008/5/13/pubmed PY - 2009/1/24/medline PY - 2008/5/13/entrez SP - 219 EP - 26 JF - The Journal of surgical research JO - J. Surg. Res. VL - 150 IS - 2 N2 - BACKGROUND: Hepatocellular cancer (HCC) is a leading cause of cancer-related death worldwide. Historically, doxorubicin (DOX) has been widely used against unresectable HCC with variable response rates. MATERIALS AND METHODS: We hypothesized that DOX combined with mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (MEK-ERK) targeted therapy may provide enhanced anti-cancer effects. Human HCC cell lines (HepG2, Hep3B) were treated with DOX and MEK enzyme inhibitors, U0126 or PD184161, alone or in combination. Growth, apoptosis, and ERK expression/MEK activity were respectively determined by proliferation assay, DNA fragmentation enzyme-linked immunoassay or fluorochrome inhibitor of caspases, and Western blot. RESULTS: DOX (0.01-1 microM) decreased cell proliferation in Hep3B cells (IC(50) approximately 0.12 microM) at 48 to 72 h; DOX was less effective in HepG2 cells (IC(50) approximately 0.25 microM). At early time points (30 min) after DOX treatment of Hep3B cells, MEK activity was unchanged at low doses and decreased at higher doses; after 24 h, phospho-ERK levels increased at higher doses. Contrarily, in HepG2 cells, DOX caused a sustained, dose-dependent increase in phospho-ERK levels at early and late time points. The MEK inhibitor U0126 decreased phospho-ERK in both HCC lines. In contrast to DOX, HepG2 cells were more sensitive than Hep3B cells to U0126. The combination of DOX with U0126 (or PD184161) resulted in greater inhibition of proliferation in HepG2 but not in Hep3B cells. This effect may be mediated in part by enhanced apoptosis. CONCLUSIONS: The effect of DOX on early and late induction of MEK activity predicts its chemotherapeutic response in HCC. Furthermore, this effect may also determine the utility of MEK inhibitor combination treatment. SN - 1095-8673 UR - https://www.unboundmedicine.com/medline/citation/18468633/The_effect_of_doxorubicin_on_MEK_ERK_signaling_predicts_its_efficacy_in_HCC_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-4804(08)00053-X DB - PRIME DP - Unbound Medicine ER -