An orally bioavailable parthenolide analogue inhibits both subcutaneous and metastatic xenograft growth in lung and bladder cancer cell lines and is independent of p53 status

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Death from lung and bladder cancer is due to chemo resistant disease and new agents are needed. Parthenolide is a naturally occurring product, which inhibits nuclear factor kappa B (NFκB) and generates reactive oxygen species (ROS) with JNK activation. However, its clinical application is limited by poor solubility. Dimethylaminoparthenolide (DMAPT) is a water-soluble analogue and reaches serum concentrations greater than 20µM in mice after oral gavage. In vitro studies with the bladder cancer cell line UMUC-3 (p53 mutant) and the non-small cell lung cancer cell line A549 (p53 wild type) have shown that it inhibits cellular proliferation and generates ROS with associated JNK activation. In addition, it induces p21 in UMUC-3 but not A549 cells. N-acetylcysteine (NAC) inhibited DMAPT induced generation of ROS as measured by flow cytometry. Moreover, DMAPT inhibits NFκB activation and reduces the expression of the NF-κB target gene TRAF-2. To determine the in vivo activity of DMAPT in solid tumors, athymic nude mice were inoculated subcutaneously with A549 cells or UMUC-3 cells in the flank. Mice were treated by daily oral gavage with mannitol (control) or DMAPT dissolved in mannitol once the xenograft was established (~ seven days after inoculation). DMAPT decreased the volume of the subcutaneous tumors by 67% in the UMUC-3 model (day 28 after implantation, 100 mg/kg twice per day). In the A549 model, 100 mg/kg once daily decreased tumor volume by 56% at day 65 after implantation. A separate in vivo metastatic model was employed using A549 cells injected into the tail vein. Treatment was initiated on day 7 post-injection and the mice were sacrificed 65 days after injection. The lungs were fixed in paraffin and stained with hematoxylin and eosin. The area of lung metastases was measured by “Bioquant” software analysis of one lung section per mouse. The readers were blinded to treatment arm. The mean area of lung metastases was decreased by 77% in the mice treated with 40 mg/kg/day of DMAPT in PBS versus control (treated with PBS alone). In conclusion, DMAPT has in vivo anti-cancer activity in both subcutaneous and lung metastasis solid tumor models. Its mechanism of action is independent of p53 and associated with both generation of ROS as well as inhibition of NFκB activity.