Targeting the IL-6 Pathway in Multiple Myeloma and its Implications in Cancer-Associated Gene Hypermethylation

    Authors

    S. B. Ingersoll; S. Ahmad; N. D. Thoni; F. H. Ahmed; K. A. Monahan;J. R. Edwards

    Comments

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    Abbreviated Journal Title

    Med. Chem.

    Keywords

    Multiple myeloma; IL-6; cell proliferation; gene expression; epigenetics; methylation; therapeutic implications; ANTI-INTERLEUKIN-6 MONOCLONAL-ANTIBODY; DNA-METHYLATION; INTERLEUKIN-6; RECEPTOR; PROGRESSION; EXPRESSION; GROWTH; Chemistry, Medicinal

    Abstract

    Aberrant methylation of tumor suppressor genes (TSG) is an important epigenetic event in cancer, including multiple myeloma (MM). Interleukin-6 (IL-6), which plays a significant role in the pathogenesis of MM, also regulates DNA methylation. However, attempts to bring IL-6 blockade to the clinic have had limited success. We hypothesize that IL-6 regulation of hypermethylation may be an important pathway leading to rational chemotherapeutic/anti-IL-6 combinations. We first studied the correlation of IL-6 expression and dependence in MM cell lines: U266B1, RPMI8226, and KAS6/1. We confirmed that KAS6/1 is IL-6-dependent whereas U266B1 and RPMI8226 cells are IL-6-independent and that blocking IL-6 inhibited the growth of U266B1 (36% inhibition; p < 0.05) and KAS6/1 (68% inhibition; p < 0.01), but not the RPMI8226 cells. Using RT-PCR, we showed that U266B1 cells express IL-6, but RPMI8226 and KAS6/1 cells do not. This IL-6 expression pattern correlates with the anti-IL-6 inhibition findings. To correlate IL-6 sensitivity with hypermethylation of TSG, we investigated promoter methylation of CDH1 and DcR1. We found that the promoter of DcR1 and CDH1 is methylated in U266B1 cells and un-methylated in RPMI8226 cells. Furthermore, the DcR1 promoter was un-methylated in KAS6/1 cells. These data support our hypothesis that an IL-6-dependent pathway may regulate hypermethylation of TSG in MM. Newer chemotherapeutic agents that affect methylation are being studied in combination with IL-6 blockade.

    Journal Title

    Medicinal Chemistry

    Volume

    7

    Issue/Number

    5

    Publication Date

    1-1-2011

    Document Type

    Article

    Language

    English

    First Page

    473

    Last Page

    479

    WOS Identifier

    WOS:000299575500014

    ISSN

    1573-4064

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