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Control of inducible chemoresistance: Enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-κB

Abstract

Programmed cell death (apoptosis) seems to be the principal mechanism whereby anti-oncogenic therapies such as chemotherapy and radiation effect their responses. Resistance to apoptosis, therefore, is probably a principal mechanism whereby tumors are able to overcome these cancer therapies. The transcription factor NF-κB is activated by chemotherapy and by irradiation in some cancer cell lines. Furthermore, inhibition of NF-κB in vitro leads to enhanced apoptosis in response to a variety of different stimuli. We show here that inhibition of NF-κB through the adenoviral delivery of a modified form of IκBα, the inhibitor of NF-κB, sensitizes chemoresistant tumors to the apoptotic potential of TNFκ and of the chemotherapeutic compound CPT-11, resulting in tumor regression. These results demonstrate that the activation of NF-κB in response to chemotherapy is a principal mechanism of inducible tumor chemoresistance, and establish the inhibition of NF-κB as a new approach to adjuvant therapy in cancer treatment.

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Figure 1: TNFα induces tumor regression when NF-κB activation is blocked.
Figure 2: Tumor regression induced by TNFα in NF-κB inhibited cells is due to apoptosis.
Figure 3: Activation of NF-κB in human fibrosarcoma cells by CPT and SN38.
Figure 4: Fibrosarcoma tumor growth inhibition in response to CPT-11 treatment and inhibition of NF-κB.
Figure 5: Induction of apoptosis by CPT-11 and inhibition of NF-κB in HT1080 fibrosarcoma tumors.

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Acknowledgements

The authors thank Y. Lin for assistance with statistical analysis. We also acknowledge J. Roth for Ad.CMV3. This work has been funded by the UNC Lineberger Comprehensive Cancer Center (J.C.C.), by the American Cancer Society Clinical Oncology Career Development Award 96-21 (J.C.C.) and by research grants CA73756, CA75080 and AI35098 (to A.S.B.) and CA75528 (to J.C.C.)from the NIH and by a Leukemia Society of America grant (to A.S.B.). Support for C.-Y.W. was provided by NIH grant DE12823. Additional support for this project was provided by the UNC SPORE program in breast cancer (NCI grant CA58223).

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Wang, CY., Cusack, J., Liu, R. et al. Control of inducible chemoresistance: Enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-κB. Nat Med 5, 412–417 (1999). https://doi.org/10.1038/7410

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