Advances in disease biology: Therapeutic implications

doi:10.1016/S0037-1963(01)90088-5

Seminars in Hematology

Volume 38, Supplement 3, April 2001, Pages 6-10

https://doi.org/10.1016/S0037-1963(01)90088-5 Get rights and content

Abstract

The survival and proliferation of multiple myeloma cells are largely dependent on a supportive microenvironment. Interleukin-6 (IL-6) is known for its ability to support cell growth and prevent apoptosis, and clinical trials using monoclonal antibodies to block IL-6 or its receptors are underway. Apoptosis of myeloma cells triggered by corticosteroids is mediated by related focal adhesion tyrosine kinase (RAFTK); blocking RAFTK inhibits this apoptosis-inducing effect IL-6 activates SHP2, which inhibits RAFTK activation, thereby protecting multiple myeloma cells from the apoptotic effects of corticosteroids. Therefore, SHP2 and RAFTK might be appropriate targets for therapeutic interventions in multiple myeloma. Angiogenesis is also prominent in the pathogenesis of multiple myeloma. Vascular endothelial growth factor (VEGF) is one of the important endogenous factors that promote angiogenesis. An understanding of the process of angiogenesis in myeloma is necessary, because its inhibition offers promising prognostic and therapeutic implications. Thalidomide has recently been found to have both antiangiogenic and immunostimulating effects, and may be an important new antimyeloma agent. Immune-based therapies will likely play an increasing role in the treatment of multiple myeloma, and novel approaches are directed to generating immune responses to specific multiple myeloma antigens.

References (11)

D Chauhan et al.
Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B
Blood
(1996)
D Chauhan et al.
SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells
J Biol Chem
(2000)
T Hideshima et al.
Thalidomide and its analogues overcome drug resistance of human multiple myeloma cells to conventional therapy
Blood
(2000)
RH Vonderheide et al.
The telomerase catalytic subunit is a widely expressed tumor associated antigen recognized by cytotoxic T lymphocytes
Immunity
(1999)
D Chauhan et al.
RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells
Oncogene
(1999)

There are more references available in the full text version of this article.

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These results show that combined treatment with bortezomib and curcumin increased apoptosis in U266 cells as compared with either compound alone. Interaction between MM cells and BMSCs triggers pro-inflammatory cytokines including IL-6, VEGF, and SDF-1α which are involved in MM cell proliferation, survival, and drug resistance (Anderson, 2001). In spite of recent therapeutic advances and development of novel drugs, MM is still an incurable disease.
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The rational designed antagonist derived from the complex structure of interleukin-6 and its receptor affectively blocking interleukin-6 might be a promising treatment in multiple myeloma
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Although IL-6 did not function as a growth factor for normal B-cells, proliferating plasma blasts, it was involved in the origin of some benign and malignant plasma cell expansions [5]. Anderson [6] considered that IL-6 was involved in the multiple myeloma (MM) pathogenesis and able to stimulate the growth of MM cells from patients. In the clinic, high levels of circulating IL-6 reflected a worse course of the disease [7].
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Advances in disease biology: Therapeutic implications

Abstract

Blood

J Biol Chem

Blood

Immunity

RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells

Oncogene