Pancreatic cancer is the third leading cause of death in the US with a poor 5-year survival rate of 8.5%. A novel anti-cancer drug, dimethylamino-parthenolide (DMAPT), is the water-soluble analog of the natural sesquiterpene lactone, parthenolide. The putative modes of action of DMAPT are inhibition of the NFκB pathway and depletion of glutathione levels; the latter causing cancer cells to be more susceptible to oxidative stress-induced cell death. Actinomycin-D is a polypeptide antibiotic that binds to DNA and inhibits RNA and protein synthesis by inhibiting RNA polymerase II. A phase 2 clinical trial indicated that Actinomycin-D could be a potent drug against pancreatic cancer; however, it was not a favored drug due to toxicity issues. New drug entities and methods of drug delivery, used alone or in combination, are needed to treat pancreatic cancer more effectively. Thus, it was postulated that combining DMAPT and Actinomycin-D would result in synergistic inhibition of Panc-1 pancreatic cancer cell growth because DMAPT's inhibition of NFκB would enhance induction of apoptosis by Actinomycin-D, via phosphorylation of c-Jun, by minimizing NFκB inhibition of c-Jun phosphorylation. Combining these two drugs induced a higher level of cell death than each drug alone. A fixed drug ratio of DMAPT: Actinomycin-D (1200:1) was used. Data from metabolic (MTT) and colony formation assays were analyzed for synergism with CompuSyn software, which utilizes the Chou-Talalay equation. The analyses indicated synergism and moderate synergism at combination concentrations of DMAPT/Actinomycin-D of 12/0.01 and 18/0.015 µM, respectively.
trans-Cyanocombretastatin A-4 (trans-CA-4) analogues have been structurally modified to afford their more stable CA-4-(2H)-1,2,3-triazole analogues. Fifteen novel, stable 4-heteroaryl-5-aryl-(2H)-1,2,3-triazole CA-4 analogues (8a–i, 9 and 11a–e) were evaluated for anti-cancer activity against a panel of 60 human cancer cell lines. These analogues displayed potent cytotoxic activity against both hematological and solid tumor cell lines with GI50 values in the low nanomolar range. The most potent compound, 8a, was a benzothiophen-2-yl analogue that incorporated a 3,4,5-trimethoxyphenyl moiety connected to the (2H)-1,2,3-triazole ring system. Compound 8a exhibited GI50 values of <10 nM against 80% of the cancer cell lines in the panel. Three triazole analogues, 8a, 8b and 8g, showed particularly potent growth inhibition against the triple negative Hs578T breast cancer cell line with GI50 values of 10.3 nM, 66.5 nM and 20.3 nM, respectively. Molecular docking studies suggest that these compounds bind to the same hydrophobic pocket at the interface of α- and β-tubulin that is occupied by colchicine and cis-CA-4, and are stabilized by Van der Waals’ interactions with surrounding amino acid residues. Compound 8a was found to inhibit tubulin polymerization in vitro with an IC50 value of 1.7 µM. The potent cytotoxicity of these novel compounds and their inhibition of tubulin dynamics make these triazole analogues promising candidates for development as anti-cancer drugs.
Viral vector-mediated gene therapies have the potential to treat many human diseases; however, host immune responses against the vector and/or the transgene pose a safety risk to the patients and can negatively impact product efficacy. Thus, novel strategies to reduce vector immunogenicity are critical for the advancement of these therapies. T cell activation (TCA) is required for the development of immune responses during gene therapy. We hypothesized that modulation of TCA by incorporating a novel viral immunomodulatory factor into a viral vector may reduce unwanted TCA and immune responses during gene therapy. To test this hypothesis, we identified an immunomodulatory domain of the hepatitis C virus (HCV) NS protein 5A (NS5A) protein and studied the effect of viral vectors expressing NS5A peptide on TCA. Lentiviral vector-mediated expression of a short 20-mer peptide derived from the NS5A protein in human T cells was sufficient to inhibit TCA. Synthetic 20-mer NS5A peptide also inhibited TCA in primary human T cells. Mechanistically, the NS5A protein interacted with Lck and inhibited proximal TCR signaling. Importantly, NS5A peptide expression did not cause global T cell signaling dysfunction as distal T cell signaling was not inhibited. Finally, recombinant adeno-associated virus (AAV) vector expressing the 20-mer NS5A peptide reduced both the recall antigen and the TCR-mediated activation of human T cells and did not cause global T cell signaling dysfunction. Together, these data suggest that expression of a 20-mer NS5A peptide by an AAV vector may reduce unwanted TCA and may contribute to lower vector immunogenicity during gene therapy.
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