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Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1749-1757
Anti-Estrogens Induce Apoptosis of Multiple Myeloma Cells
Steven P. Treon,
Gerrard Teoh,
Mitsuyoshi Urashima,
Atsushi Ogata,
Dharminder Chauhan,
Iain J. Webb, and
Kenneth C. Anderson
From the Department of Adult Oncology, Dana-Farber Cancer Institute,
Boston, MA; the Division of Medical Oncology, the Massachusetts General
Hospital, Boston, MA; the Department of Medicine, Harvard Medical
School, Boston, MA; and the Department of Haematology, Singapore
General Hospital, Singapore.
Previous studies have suggested that multiple myeloma (MM) cells
express estrogen receptors (ER). In the present study, we characterized
the effects of estrogen agonists and antagonists (anti-estrogens
[AE]) on growth of MM cell lines and MM patient cells. In addition to
antagonizing estrogen binding to ER, AE can trigger apoptosis. Hence,
we also determined whether estrogens or AE altered MM cell survival.
Immunoblotting showed that ER- is expressed in 4 of 5 MM cell lines
(ARH-77, RPMI 8226, S6B45, and U266, but not OCI-My-5 cells), as well
as in freshly isolated MM cells from 3 of 3 patients. 17 -estradiol
(E2) did not significantly alter proliferation of MM cell lines or MM
patient cells. In contrast, two structurally distinct AE, tamoxifen
(TAM) and ICI 182,780 (ICI), significantly inhibited the proliferation
of all 5 MM cell lines and MM cells from 2 of 2 patients
(IC50, 2 to 4 µmol/L). Proliferation of these cell lines
was also inhibited by the hydroxylated TAM derivative,
4-hydroxytamoxifen (4HTAM), although this derivative was less potent
than TAM (IC50, 3 to 25 µmol/L). In contrast, the
dehalogenated TAM derivative toremifene (TOR) did not inhibit MM cell
proliferation. We next examined the effects of these agents on MM cell
survival. TAM, ICI, and, to a lesser extent, 4HTAM and TOR triggered
apoptosis in both ER--positive as well as ER--negative MM cell
lines and patient MM cells, evidenced both by fluorescence-activated cell sorting (FACS) analysis using propidium iodide
staining and the TUNEL assay. TAM-induced growth inhibition and
apoptosis of ER--positive S6B45 MM cells was not blocked by
coculture with excess E2. TAM-induced apoptosis of S6B45 MM cells was
also unaffected by addition of exogenous interleukin-6. Importantly,
both the inhibition of MM cell proliferation and the induction of MM
cell apoptosis were achieved at concentrations of TAM (0.5 and 5.0 µmol/L) that did not significantly alter in vitro growth of normal hematopoietic progenitor cells. Similar plasma levels of TAM have been
achieved using high-dose oral TAM therapy, with an acceptable toxicity
profile. These studies therefore provide the rationale for trials to
define the utility of AE therapy in MM.
© 1998 by The American Society of Hematology.
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