Sensitization of multiple myeloma and B lymphoma lines to dexamethasone and γ-radiation-induced apoptosis by CD40 activation

Author： Zhou Zhao-Hua Zhou Z-H. Shi Q. Shi Qin Wang Jiang-Fang Chen Yong- Zhuang Yu-Mei Pan Jian-Zhong Xu Chang-Shao Qi Chun-Jian Zhang Xue-Guang

Publisher： Springer Publishing Company

ISSN： 1360-8185

Source： Apoptosis, Vol.10, Iss.1, 2005-01, pp. : 123-134

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Abstract

We examined the effects of CD40 activation with dexamethasone (Dex) or ⁶⁰Co-γ-irradiation on the growth of malignant B cells in vitro, using the human multiple myeloma (MM) cell line, XG2, and the B lymphoma Daudi cell line as models. Both lines are resistant to Dex and irradiation; 10⁻⁷M Dex or 10 Gy of γ-irradiation induced only minimal growth arrest and apoptosis of the cells. Treatment of the cells with the agonistic anti-CD40 monoclonal antibody 5C11 partially inhibited the proliferation of the Daudi cells; XG2 underwent apoptosis. XG2 is an Interleukin-6 (IL-6)-dependent myeloma cell line and CD40 activation blocked XG2 in the G1 phase of the cell cycle, in a manner similar to the effect of IL-6 deprivation. Daudi was blocked in the G2/M phase after treatment with the agonistic CD40 mAb 5C11. Furthermore, the activation of CD40 on Daudi and XG2 enhanced their sensitivity to dexamethasone-and γ -irradiation -induced growth arrest and apoptosis. CD40 activation stimulated both anti-apoptotic Bcl-XL and pro-apoptotic Bax mRNA synthesis in the Daudi cell line; CD40 activation increased the Bax mRNA level but had no effect on the Bcl-XL mRNA level in the XG2 cell line. Apoptosis in both cell lines was associated with an increasing ratio of Bax-to-Bcl-XL both in mRNA and in protein levels. It is concluded that use of the anti-CD40 mAb 5C11 either by itself or in combination with chemotherapy and/or radiotherapy may have significant therapeutic potential.