Anti-proliferative activity of novel amidoximes in human and murine malignant cell lines and in mouse mammary carcinoma
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Cancer incidence and mortality is on the rise worldwide, which necessitates newer and more potent therapies to combat cancer. In this study, four novel amidoximes, JJMB5, JJMB6, JJMB7 and JJMB9, were analyzed for their ability to inhibit proliferation of human and murine malignant cell lines, and in mouse mammary carcinoma. We established that JJMB5 and JJMB6 induced inhibition of acetylation of core histones H3K9 and H4K5 prior to apoptosis. Moreover, JJMB5, JJMB6 and JJMB9 inhibited acetylation of core histone H3K27, but JJMB7 did not. Additionally, JJMB5, JJMB7 and JJMB9 inhibited the proliferation of murine mammary malignant cell lines in culture but did not inhibit mouse embryonic fibroblasts, as established by the MTS colorimetric assay. When human and murine malignant cell lines were treated individualy, or in combination of various amidoximes or amidoximes with cisplatin, several combination treatments resulted in significantly lower growth inhibitory concentration (GI50) compared to individual treatments. Once the MTDs for the amidoximes were established, tumor studies were carried out. Results on tumor volume reduction were mixed. For example, mice treated with JJMB7 demonstrated significant tumor volume reduction in the first experiment but not in subsequent experiments. On the other hand, mice treated with JJMB9 had the lowest tumor volumes in all experiments. In The second experiment, tumor volumes were significant up to day 21. There were no differences in lung metastasis area between the treatment groups. Acetylation studies of 4T1 cells from tumors revealed that JJMB9 induced significant inhibition of acetylation of H4K5. Also, JJMB9 was able to induce drug resistance in MCF-7 cells, and this resistance was reversed by cisplatin. The amidoximes have potential if certain changes can be made on the protocol such as decreasing 4T1 cells implanted into the mammary fat pad, amidoxime dose escalation, and using alternate routes of administration.