Defects in the apoptotic machinery of cancer cells: role in drug resistance

https://doi.org/10.1016/S1044-579X(02)00130-XGet rights and content

Abstract

The therapeutic goal in cancer treatment is to trigger tumor-selective cell death. Since many antineoplastic agents induce an apoptotic type of death in susceptible cells, it is likely that dysfunction of the apoptotic machinery might be an important determinant of resistance to anticancer drugs. Here we review known differences in the apoptotic machinery in cancer cells, and how this knowledge can be used to increase the efficiency of tumor treatment.

Introduction

Various forms of chemotherapy and ionizing radiation represent the main weapons used to kill tumor cells. Although successful treatment of many hematological and childhood malignancies has been achieved, the most common tumors (especially solid tumors) are still resistant to these types of treatment. Therefore, it is clear that the development of new therapies based on modern knowledge of tumorigenesis, mechanisms of tumor cell death, and resistance to treatment is one of the important areas in biomedical research.

The therapeutic goal in cancer is to trigger tumor-selective cell death (for review see [1], [2]). In principle, there are at least two strategies to achieve this goal. Firstly, it is important to deliver the drug to the tumor-containing tissue in a manner that favors its accumulation in cancer cells. Secondly, it is important to selectively activate the cell death machinery of tumor cells and thus spare normal cells and tissues. Here, we would like to discuss differences in efficiency of the apoptotic machinery in cancer cells and how to use this knowledge to increase the sensitivity of tumor cells to treatment.

Section snippets

The composition of the apoptotic machinery

There are thousands of biological, chemical and physical agents that can cause cell death. Most of these agents induce either apoptosis or necrosis in a dose-dependent manner. Intriguingly, despite the multitude of intracellular targets for the different triggers, many of these agents induce apoptosis through the activation of just a few common pathways (Fig. 1).

Does dysregulation of apoptosis play any role in resistance of tumor cells to treatment?

Anticancer drugs are designed to kill tumor cells via activation of the cellular death machinery. However, in spite of this tumor cells often remain alive and continue to grow. How do tumor cells evade drug-induced apoptosis? Which anti-apoptotic mechanisms are activated in malignant cells? Is it possible to bypass these mechanisms to improve the sensitivity of tumor cells to treatment? All these questions remain to be answered.

Concluding remarks

The ability of malignant cells to evade apoptosis is a hallmark of cancer, and their resistance to apoptosis constitutes an important clinical problem [1]. Cell death pathways in tumor cells appear to be much more complicated than was originally anticipated. Resistance of many tumors to chemotherapy is associated with either defects or dysregulation of different steps within the cell death machinery (Table 1). None of the components of this machinery operates in isolation, and the activation of

Acknowledgements

Work in the authors’ laboratory is supported by grants from the Swedish Medical Research Council (03X-2471), and the Swedish (3829-B01-06XAC) and Stockholm (02:145) Cancer Societies. Many thanks to Dr. J.D. Robertson for stimulating discussions and for carefully reading the manuscript. We apologize to those authors whose primary references were not cited due to space limitations.

References (82)

  • B. Liu et al.

    A novel single amino acid deletion caspase-8 mutant in cancer cells that lost pro-apoptotic activity

    J. Biol. Chem.

    (2002)
  • M.S. Shin et al.

    Inactivating mutations of CASP10 gene in non-Hodgkin lymphomas

    Blood

    (2002)
  • S. Hu et al.

    I-Flice, a novel inhibitor of tumor necrosis factor receptor-1- and CD-95-induced apoptosis

    J. Biol. Chem.

    (1997)
  • N. Mitsiades et al.

    Intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human multiple myeloma cells

    Blood

    (2002)
  • T.F. Burns et al.

    Identification of inhibitors of TRAIL-induced death (ITIDs) in the TRAIL-sensitive colon carcinoma cell line SW480 using a genetic approach

    J. Biol. Chem.

    (2001)
  • F. Cecconi et al.

    Apaf-1 (CED-4 homolog) regulates programmed cell death in mammalian development

    Cell

    (1998)
  • L. Jia et al.

    Apaf-1 protein deficiency confers resistance to cytochrome c-dependent apoptosis in human leukemic cells

    Blood

    (2001)
  • B.B. Wolf et al.

    Defective cytochrome c-dependent caspase activation in ovarian cancer cell lines due to diminished or absent apoptotic protease activating factor-1 activity

    J. Biol. Chem.

    (2001)
  • D.W. Seol et al.

    A caspase-9 variant missing the catalytic site is an endogenous inhibitor of apoptosis

    J. Biol. Chem.

    (1999)
  • P.A. Svingen et al.

    Evaluation of Apaf-1 and pro-caspases-2, -3, -7, -8, and -9 as potential prognostic markers in acute leukemia

    Blood

    (2000)
  • J. Ekedahl et al.

    Expression of inhibitor of apoptosis proteins in small-and non-small-cell lung carcinoma cells

    Exp. Cell Res.

    (2002)
  • S.S. Liu et al.

    Anti-apoptotic proteins, apoptotic and proliferative parameters and their prognostic significance in cervical carcinoma

    Eur. J. Cancer

    (2001)
  • C.G. Ferreira et al.

    Assessment of IAP (inhibitor of apoptosis) proteins as predictors of response to chemotherapy in advanced non-small-cell lung cancer patients

    Ann. Oncol.

    (2001)
  • F. Guo et al.

    Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis

    Blood

    (2002)
  • D. Vucic et al.

    SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP)

    J. Biol. Chem.

    (2002)
  • D. Chauhan et al.

    Apaf-1/cytochrome c-independent and Smac-dependent induction of apoptosis in multiple myeloma (MM) cells

    J. Biol. Chem.

    (2001)
  • Y. Suzuki et al.

    A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death

    Mol. Cell

    (2001)
  • T.J. Kottke et al.

    Lack of correlation between caspase activation and caspase activity assays in paclitaxel-treated MCF-7 breast cancer cells

    J. Biol. Chem.

    (2002)
  • Y. Kawabata et al.

    Defective apoptotic signal transduction pathway downstream of caspase-3 in human B-lymphoma cells: a novel mechanism of nuclear apoptosis resistance

    Blood

    (1999)
  • J. Chandra et al.

    Resistance of leukemic cells to 2-chlorodeoxyadenosine is due to a lack of calcium-dependent cytochrome c release

    Blood

    (2002)
  • D. Hanagan et al.

    The hallmarks of cancer

    Cell

    (2000)
  • F.H. Igney et al.

    Death and anti-death: tumor resistance to apoptosis

    Nat. Rev. Cancer

    (2002)
  • A. Ashkenazi

    Targeting death and decoy receptors of the tumour-nectosis factor superfamily

    Nat. Rev. Cancer

    (2002)
  • M. Karin et al.

    NF-kB at the crossroads of life and death

    Nat. Immunol.

    (2002)
  • P. Lassus et al.

    Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization

    Science

    (2002)
  • K.H. Vousden et al.

    Live or let die: the cell’s response to p53

    Nat. Rev. Cancer

    (2002)
  • D.W. Nicholson

    Caspase structure, proteolytic substrates, and function during apoptotic cell death

    Cell Death Differ.

    (1999)
  • X. Li et al.

    TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2

    Nature

    (2002)
  • A.M. Verhagen et al.

    Inhibitor of apoptosis proteins and their relatives: IAPs and other BIRPs

    Genome Biol.

    (2001)
  • H. Okada et al.

    Generation and characterization of Smac/DIABLO-deficient mice

    Mol. Cell Biol.

    (2002)
  • C. Friesen et al.

    Cytotoxic drugs and the CD-95 pathway

    Leukemia

    (1999)
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