Actinomycin‐D and dimethylamino‐parthenolide synergism in treating human pancreatic cancer cells

Abstract

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.

Natural Products Impacting DNA Methyltransferases and Histone Deacetylases

“…This inhibition is thought to be due to its gamma methylene lactone which probably alkylates the proximal thiolate of Cys 1226 of the catalytic domain ( Liu et al, 2009a ). Recently, a new parthenolide derivative, dimethylamino-parthenolide, has been reported to inhibit the Nuclear chain factor kappa‐light‐chain enhancer of activated B cells (NF-κB) pathway and causes depletion of glutathione levels; the latter causing cancer cells to be more susceptible to oxidative stress‐induced cell death ( Pei et al, 2009 ; Lamture et al, 2018 ). This result highlights the potential role of this drug as a chemopreventive agent and in epigenetic cancer therapy.…”

“…This result highlights the potential role of this drug as a chemopreventive agent and in epigenetic cancer therapy. Recently, it has been demonstrated that combination of the anticancer drug actinomycin-D, which functions by intercalating into DNA, and dimethylamino-parthenolide results in a synergistic inhibition of Panc‐1 pancreatic cancer cell growth ( Lamture et al, 2018 ). However, the potential clinical use of parthenolide is still not clear.…”

Emerging agents that target signaling pathways in cancer stem cells

“…Lung cancer Preclinical December 3, 2019 AD has hepatoxicity, and TS is without toxic side effects in nude mice [29,30] signaling pathway in preclinical experiments. For example, XAV939 can inhibit β-catenin signaling and thus attenuate CSC progression by interacting with the terminal anchor polymerase-binding domain (TBD) in Axin [40], which can abrogate CSC-mediated chemoresistance in head and neck squamous cell carcinoma (HNSCC) and colon cancer cells [41,42].…”

Parthenolide as Cooperating Agent for Anti-Cancer Treatment of Various Malignancies

“…A phase 2 clinical trial has shown that actinomycin-D could be an effective drug in the pancreatic cancer treatment; however, it has substantial dose-limiting toxic side effects [167]. Actinomycin-D combined with DMAPT synergistically enhanced cell death of pancreatic cancer cells and may provide an effective treatment at lower doses [168].…”