Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and γ-irradiation

Damiano, Jason S.; Hazlehurst, Lori A.; Dalton, William S.

doi:10.1038/sj.leu.2402179

Cited by 173 publications

(117 citation statements)

References 39 publications

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“…18,19,24 In the present study, we investigated whether live BMSCs would influence the response of myeloma cells to the topoisomerase II inhibitor mitoxantrone. Although mitoxantrone is used less frequently than doxorubicin as an antimyeloma drug, it has been extensively characterized as a classic topoisomerase II inhibitor, and does not possess the fluorescent features of doxorubicin.…”

Section: Resultsmentioning

confidence: 99%

Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms

2003

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The tumor microenvironment plays a critical role in determining the fate of tumor cells. We have previously reported that adhesion of human myeloma and leukemia cell lines to the extracellular matrix protein, fibronectin, confers a multidrugresistant phenotype. Mechanisms associated with this cell adhesion-mediated drug resistance are drug-type specific. In the present study, we examined the influence of bone marrow stromal cells (BMSCs) on myeloma cell response to the topoisomerase II inhibitor, mitoxantrone. Apoptosis was inhibited by more than 50% when cells were adhered to BMSCs as compared to myeloma cells maintained in suspension. To investigate the mechanisms contributing to the resistance of myeloma cells in contact with BMSCs, we examined the protective effects of BMSCs under four separate conditions:(1) direct cell contact; (2) BMSCs conditioned medium; (3) medium conditioned by coculturing myeloma cells in direct contact with BMSCs; and (4) medium conditioned by coculturing myeloma cells and BMSCs without direct physical contact. Conditioned medium from BMSCs alone was not sufficient to protect myeloma cells from drug-induced apoptosis; however, soluble factors produced during the myeloma-BMSCs interaction decreased the sensitivity of myeloma cells to mitoxantrone, suggesting a dynamic interaction between myeloma cells and BMSCs. We also found that myeloma cells in direct contact with BMSCs underwent growth arrest, whereas soluble factors produced by myeloma cells-BMSCs coincubation stimulated the proliferation of myeloma cells. These data show that both cell-cell adhesion of BMSCs with myeloma cells and soluble factors induced by this cell-cell interaction are involved in the protection of myeloma cells from mitoxantrone-induced apoptosis; however, the mechanisms contributing to the drug resistance are different.

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Section: Resultsmentioning

confidence: 99%

Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms

2003

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“…For example, the culture of a5b1-integrinexpressing cells on Fn is associated with increased expression of the antiapoptotic protein Bcl2 and thus protects these cells from apoptosis (Zhang et al, 1995). Similarly, several cancer cell lines have been shown to better survive chemotherapy or radiation-induced cell death when cultured on Fn-coated surfaces (Damiano et al, 1999(Damiano et al, , 2001Aoudjit and Vuori, 2001;Cordes et al, 2003;Korah et al, 2004). The crosstalk between the cell surface a5b1-integrin and Fn leads to the activation of signaling pathways that can induce cell growth and contribute to the development of the metastatic phenotype (Parise et al, 2000;Mehlen and Puisieux, 2006).…”

Section: Discussionmentioning

confidence: 99%

Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells

et al. 2006

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Distant metastasis is frequently observed in patients with breast cancer and is a major cause of cancer-related deaths in these patients. Currently, very little is known about the mechanisms that underlie the development of the metastatic phenotype in breast cancer cells. We previously found that metastatic breast cancer cells express high levels of tissue transglutaminase (TG2), but established no direct link between TG2 and metastasis. In this study, we hypothesized that TG2 plays a role in conferring the metastatic phenotype to breast cancer cells. The results obtained suggested that increased expression of TG2 in breast cancer cells contributes to their increased survival, invasion and motility. We further found that TG2 protein in a metastatic breast cancer MDA-MB231 cells was present on the cell surface in close association with integrins b1, b4 and b5. Downregulation of endogenous TG2 by small interfering RNA inhibited fibronectin (Fn)-mediated cell attachment, survival and invasion. Conversely, ectopic expression of TG2 augmented invasion of breast cancer cells and attachment to Fn-coated surfaces. We conclude that TG2 expression in breast cancer cells plays an important role in the development of the metastatic phenotype.

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“…Recently, an important series of papers has been published in Leukemia which document the efficacy of treatment of leukemic cells with inhibitors, which target specific signal transduction pathways. [53][54][55][56][57][58][59][60][61] Targeted cancer therapy provides promise to reduce the devastating toxic side effects of nonspecific chemotherapy.…”

Section: Figurementioning

confidence: 99%

Requirement for the PI3K/Akt pathway in MEK1-mediated growth and prevention of apoptosis: identification of an Achilles heel in leukemia

et al. 2003

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Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and γ-irradiation

Cited by 173 publications

References 39 publications

Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms

Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms

Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells

Requirement for the PI3K/Akt pathway in MEK1-mediated growth and prevention of apoptosis: identification of an Achilles heel in leukemia

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