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

    Authors: contact us about adding a copy of your work at [email protected]

    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

    Share

    COinS
     

    Accessibility Statement

    This item was created or digitized prior to April 24, 2027, or is a reproduction of legacy media created before that date. It is preserved in its original, unmodified state specifically for research, reference, or historical recordkeeping. In accordance with the ADA Title II Final Rule, the University Libraries provides accessible versions of archival materials upon request. To request an accommodation for this item, please submit an accessibility request form.