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2014 ; 110
(9
): 2224-31
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Small molecule MIRA-1 induces in vitro and in vivo anti-myeloma activity and
synergizes with current anti-myeloma agents
#MMPMID24691427
Saha MN
; Chen Y
; Chen MH
; Chen G
; Chang H
Br J Cancer
2014[Apr]; 110
(9
): 2224-31
PMID24691427
show ga
BACKGROUND: Small molecule MIRA-1 induced mutant p53-dependent apoptosis in
several types of solid tumours. However, anti-tumour activity of MIRA-1 in
haematological malignancies including multiple myeloma (MM) is unknown. In this
study, we evaluated the effect of MIRA-1 in MM. METHODS: We examined the
anti-tumour activity of MIRA-1 alone or in combination with current anti-myeloma
agents in a panel of MM cell lines, primary MM samples, and in a mouse xenograft
model of MM. RESULTS: MIRA-1 treatment resulted in the inhibition of viability,
colony formation, and migration and increase in apoptosis of MM cells
irrespective of p53 status accompanied by upregulation of Puma and Bax and
downregulation of Mcl-1 and c-Myc. Genetic knockdown of p53 did not abrogate
apoptotic response of MIRA-1. MIRA-1 triggered activation of PERK and IRE-?
leading to splicing of XBP1 indicating an association of endoplasmic reticulum
stress response. Furthermore, combined treatment of MIRA-1 with dexamethasone,
doxorubicin or velcade displayed synergistic response in MM cells. Importantly,
MIRA-1 alone or in combination with dexamethasone retarded tumour growth and
prolonged survival without showing any untoward toxicity in the mice bearing MM
tumour. CONCLUSIONS: Our data provide the preclinical framework for clinical
evaluation of MIRA-1 as a novel therapeutic agent to improve patient outcome in
MM.