Bcl-2 and Bcl-xL are important for the induction of paclitaxel resistance in human hepatocellular carcinoma cells

doi:10.1016/j.bbrc.2004.01.118

Biochemical and Biophysical Research Communications

Volume 315, Issue 3, 12 March 2004, Pages 771-779

https://doi.org/10.1016/j.bbrc.2004.01.118 Get rights and content

Abstract

In this study we have investigated the mechanism underlying resistance to the chemotherapeutic drug paclitaxel in tumors of hepatocellular carcinoma (HCC) patients. Treatment with paclitaxel led to potent inhibition of growth of Hep3B hepatoma cells, but did not affect the growth properties of SNU-368 and SNU-398 cell lines that were established from primary HCC tumors. The growth inhibitory effect induced by paclitaxel correlated with levels of intracellular p21 and resulted in cell cycle arrest at the G2/M phase. However, paclitaxel treatment did not alter intracellular p53 levels. Instead, SNU-398 cells express high levels of the anti-apoptotic Bcl-2 and Bcl-x_L proteins and the level of Bcl-x_L could be further induced upon paclitaxel treatment. In contrast, Hep3B cells express pro-apoptotic members of the Bcl family and fail to induce Bcl-x_L upon paclitaxel treatment. Therefore, these results strongly suggest that Bcl-2 and Bcl-x_L play an important role in mediating resistance to paclitaxel.

Section snippets

Materials and methods

Cell lines. Hep3B cells were purchased from the American Type Culture Collection (ATCC, Rockville, MD). SNU-398 and SNU-368 hepatoma cell lines were purchased from the Korean Cell Line Bank (Seoul, Korea) [38], [39], [40]. These cell lines were maintained in Dulbecco’s modified Eagle’s medium (DMEM; Flow Laboratories) supplemented with 10% fetal bovine serum/glutamine/antibiotics in a humidified atmosphere of 5% CO₂ at 37 °C.

Reagents. Paclitaxel was purchased from Sigma (St. Louis, MO).

Selective sensitivity of human hepatoma cells to paclitaxel

It is known that cancer cells develop resistance to chemotherapeutic drugs through a variety of mechanisms. However, biochemical events underlying the development of resistance, especially in hepatocellular carcinoma, have not been adequately explored. To investigate resistance mechanisms against paclitaxel in hepatocellular carcinoma cells, we selected three hepatoma cell lines; Hep3B, as a well-characterized control hepatoma cell, and SNU-398 and SNU-368 as representatives of cancer cells

Discussion

There is increasing evidence of the chemotherapeutic potential of paclitaxel in the treatment of a variety of cancers such as ovarian, breast, lung, head and neck, and bladder carcinoma. However, chemotherapy with paclitaxel often fails due to acquired or innate resistance of cancer cells. A variety of mechanisms have been proposed to explain the development of resistance to anticancer drugs including increased efflux of the chemotherapeutic agent, and mutation or modification of the target

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^☆: Abbreviations: P-gp, P-glycoprotein; HCC, human hepatocellular carcinoma; DMEM, Dulbecco’s modified Eagle’s medium; CPT, camptothecin.

View full text

Bcl-2 and Bcl-xL are important for the induction of paclitaxel resistance in human hepatocellular carcinoma cells☆

Abstract

Section snippets

Materials and methods

Selective sensitivity of human hepatoma cells to paclitaxel

Discussion

Blood

Cell Biol. Int.

Biochem. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

Gynecol. Oncol.

Cancer Lett.

Exp. Cell Res.

The development and clinical utility of the taxane class of antimicrotubule chemotherapy agents

Annu. Rev. Med.

Pharmacodynamics of taxol in human head and neck tumors

Cancer Res.

Taxol induces internucleosomal DNA fragmentation associated with programmed cell death in human myeloid leukemia cells

Leukemia

CDK4 down-regulation induced by paclitaxel is associated with G1 arrest in gastric cancer cells

Clin. Cancer Res.

Paclitaxel-induced apoptosis in human gastric carcinoma cell lines

Cancer

Differential effect of taxol in rat primary and metastatic prostate tumors: site-dependent pharmacodynamics

Pharm. Res.

Paclitaxel is an effective antiproliferative agent on the human NCI-H295 adrenocortical carcinoma cell line

Chemotherapy

Effects of taxol on the human NCI-H295 adrenocortical carcinoma cell line

Endocr. Res.

Combined effect of alkyl-lysophospholipid and vincristine on proliferation, migration and invasion in human glioma cell lines in vitro

Anticancer Res.

Proliferation, migration and invasion of human glioma cells exposed to paclitaxel (Taxol) in vitro

Br. J. Cancer

Phase III trial of fluorouracil, interferon Alfa-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer

J. Clin. Oncol.

Colchicine promotes a change in chromosome structure without loss of sister chromatid cohesion in prometaphase I-arrested bivalents

Chromosoma

Structure of the alpha beta tubulin dimer by electron crystallography

Nature

Possible mechanisms of paclitaxel-induced apoptosis

Biochem. Pharmacol.

Relationship of mitotic arrest and apoptosis to antitumor effect of paclitaxel

J. Natl. Cancer Inst.

Kinetics of mitotic arrest and apoptosis in murine mammary and ovarian tumors treated with taxol

Cancer Chemother. Pharmacol.

Bcl-2 and Bcl-x_L are important for the induction of paclitaxel resistance in human hepatocellular carcinoma cells☆