Abstract
JKA97, a benzylidene analog of harmine, has been found to be a promising drug candidate for human cancer therapy, although the underlying molecular mechanisms have not been fully demonstrated. In this study, we evaluated the effects of JKA97 on human breast cancer cells in vitro and in vivo. JKA97 inhibited the growth and proliferation of MCF7 (p53 wild-type), MCF7 (p53 knockdown), and MDA-MB-468 (p53 mutant) cells in a dose-dependent manner. Treatment with JKA97 arrested breast cancer cells in G1 phase and induced apoptosis. JKA97 also significantly suppressed the growth of MCF7 and MDA-MB-468 xenograft tumors. It regulated the expression levels of G1 phase regulators, such as p21, p27, cyclinE, and cylinD1. JKA97 activated p21 transcription, independent of p53, but had little effect on p21 protein stability/degradation. In summary, our results suggest that JKA97 inhibits human breast cancer cell growth through activating p21, independent of p53, which provides a basis for developing this compound as a novel drug for human breast cancer therapy.
Highlights
Breast cancer is one of the most commonly diagnosed cancers and the leading causes of cancer death in women worldwide
The study highlights several important points: 1) JKA97 significantly inhibits breast cancer cell growth; 2) JKA97 induces cell apoptosis; 3) inhibition of cell proliferation and cell cycle progression appear to be major mechanism by which JKA97 exerts its anti-cancer effects; 4) JKA97 up-regulates p21 expression at the transcriptional level, rather than post-transcriptional level, independent of p53; and 5) JKA97 decreases the growth of human breast cancer xenograft tumors in mice, in a dose-dependent manner
MTT assay represents the total cell survival, which may be affected by various factors, at least including cell proliferation, apoptosis, and cell cycle progression
Summary
Breast cancer is one of the most commonly diagnosed cancers and the leading causes of cancer death in women worldwide. According to statistical data from GLOBOCAN, about 1.38 million new patients were diagnosed with breast cancer and about 458,400 died worldwide from the disease in 2008 [1]. In the past two decades, death rates from breast cancer have declined due to early detection, increased awareness and improved or novel therapies. Patients with advanced-stage or relapsed breast cancer often show modest response to clinically existing therapies and may even exhibit resistance to conventional chemotherapeutic agents [2,3,4]. The paucity and inefficacy of practicable therapeutics makes successful treatment of breast cancer a challenge and necessitates the discovery of alternative chemotherapeutic drugs with novel anti-cancer mechanisms
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