A water soluble parthenolide analog suppresses in vivo tumor growth of two tobacco‐associated cancers, lung and bladder cancer, by targeting NF‐κB and generating reactive oxygen species

Abstract

Dimethylaminoparthenolide (DMAPT) is a water soluble parthenolide analog with preclinical activity in hematologic malignancies. Using non-small lung cancer (NSCLC) cell lines (A549 and H522) and an immortalized human bronchial epithelial cell line (BEAS2B) and TCC cell lines (UMUC-3, HT-1197 and HT-1376) and a bladder papilloma (RT-4), we aimed to characterize DMAPT's anticancer activity in tobacco-associated neoplasms. Flow cytometric, electrophoretic mobility gel shift assays (EMSA), and Western blot studies measured generation of reactive oxygen species (ROS), inhibition of NFjB DNA binding, and changes in cell cycle distribution and apoptotic proteins. DMAPT generated ROS with subsequent JNK activation and also decreased NFjB DNA binding and antiapoptotic proteins, TRAF-2 and XIAP. DMAPT-induced apoptotic cell death and altered cell cycle distribution with upregulation of p21 and p73 levels in a cell type-dependent manner. DMAPT suppressed cyclin D1 in BEAS2B. DMAPT retained NFjB and cell cycle inhibitory activity in the presence of the tobacco carcinogen nitrosamine ketone, 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Using a BrdU accumulation assay, 5-20 lM of DMAPT was shown to inhibit cellular proliferation of all cell lines by more than 95%. Oral dosing of DMAPT suppressed in vivo A549 and UMUC-3 subcutaneous xenograft growth by 54% (p 5 0.015) and 63% (p < 0.01), respectively, and A549 lung metastatic volume by 28% (p 5 0.043). In total, this data demonstrates DMAPT's novel anticancer properties in both early and late stage tobacco-associated neoplasms as well as its significant in vivo activity. The data provides support for the conduct of clinical trials in TCC and NSCLC.In the United States in 2008, over 68,000 individuals were diagnosed with bladder cancer, and more than 14,000 patients died from their disease. Transitional cell carcinoma (TCC) is the dominant histology in over 95% of cases.1 There were also more than 200,000 patients diagnosed with lung cancer with 160,390 deaths and non-small lung cancer (NSCLC) makes up more than three quarters of these cases. Tobacco smoking is a major modifiable risk factor for both bladder and NSCLCs and significant achievements in decreasing this risk factor have been made in some countries. Despite this progress, these cancers are still a major cause of the current death rate from cancer.2 Modest advances have recently been made in the treatment of NSCLC with epidermal growth factor receptor and angiogenesis inhibition. 3,4 Therefore, novel strategies are needed to prevent the progression of epithelial cells which have entered the neoplastic

Pharmacological Dual Inhibition of Tumor and Tumor-Induced Functional Limitations in a Transgenic Model of Breast Cancer

“…DMAPT is a water-soluble analogue of parthenolide, an active ingredient of the herb feverfew (22,27). As with many targeted therapies, DMAPT displays NF-κB-dependent and NF-κB-independent activities; however, its major therapeutic effects are likely through NF-κB inhibition (22).…”

Radio-sensitization of the murine osteosarcoma cell line LM8 with parthenolide, a natural inhibitor of NF-κB

“…Despite widely documented anti-cancer activity and the absence of major adverse effects, clinical development of parthenolide is hampered by its poor water solubility, (35) thus limiting its potential as a promising clinical agent. Previous studies investigated the in vitro and in vivo activities of the water-soluble parthenolide analogue dimethylaminoparthenolide (DMAPT) (20,35,36) and reported that this analogue suppressed tumor growth by targeting NF-κB and generating reactive oxygen (37)(38)(39). The water-soluble parthenolide analogue may become a more readily available radio-sensitizing agent, but further investigation is needed to elucidate its efficacy and spectrum as a radio-sensitizing agent.…”

The role of oxidative stress in anticancer activity of sesquiterpene lactones

“…Pharmacologic experiments using both mouse xenograft models and spontaneous acute canine leukemias demonstrated its high in vivo bioactivity (Guzman et al 2007). Further in vivo studies demonstrated that DMAPT significantly suppressed the growth of prostate (Shanmugam et al 2010), lung, bladder (Shanmugam et al 2011), and breast cancers (D'Anneo et al 2013). Moreover, it inhibited metastasis in mouse xenograft model of breast cancer and enhanced survival of the treated mice.…”