Potentin vitroandin vivoanticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A

Abstract

We report here that des-methyl, des-amino pateamine A (DMDA-PatA), a structurally simplified analogue of the marine natural product pateamine A, has potent antiproliferative activity against a wide variety of human cancer cell lines while showing relatively low cytotoxicity against nonproliferating, quiescent human fibroblasts. DMDAPatA retains almost full in vitro potency in P-glycoprotein-overexpressing MES-SA/Dx5-Rx1 human uterine sarcoma cells that are significantly resistant to paclitaxel, suggesting that DMDA-PatA is not a substrate for P-glycoprotein-mediated drug efflux. Treatment of proliferating cells with DMDA-PatA leads to rapid shutdown of DNA synthesis in the S phase of the cell cycle. Cell-free studies show that DMDA-PatA directly inhibits DNA polymerases α and γ in vitro albeit at concentrations considerably higher than those that inhibit cell proliferation. DMDA-PatA shows potent anticancer activity in several human cancer xenograft models in nude mice, including significant regressions observed in the LOX and MDA-MB-435 melanoma models. DMDA-PatA thus represents a promising natural product-based anticancer agent that warrants further investigation.

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

“…In particular, cells transformed with the Ras oncogene show increased sensitivity to PatAinduced apoptosis [130]. Synthetic derivatives of PatA are also promising anti-cancer agents as the simplified PatA analog, des-methyl, desamino PatA (DMDA-PatA) is not as sensitive to the presence of multidrug resistance protein 1 (MDR1) and shows potent anti-proliferative activity in vitro against a wide variety of human cancer cell lines [131]. However, in vivo, the activity of DMDA-PatA appears more restricted as it is cytotoxic against melanoma xenograft models but not towards pancreatic or colorectal xenograft models [131].…”

“…2B). As a result, this has paved the way for the generation of synthetic derivatives of PatA, including DMDA-PatA, which has been found to possess anti-neoplastic activity in several human cancer cell lines and xenograft mouse models [131]. While these derivatives have the advantage of possessing a simpler and more efficient synthesis strategy, there has yet to be a synthetic analog exhibiting improved potency over PatA [133].…”

SAMD9 Is an Innate Antiviral Host Factor with Stress Response Properties That Can Be Antagonized by Poxviruses

“…We next examined SAMD9 protein behavior under cellular stress conditions that either stimulated (sodium arsenate [SA] treatment at 1 mM for 1 h) or were independent of (desmethyl desamino pateamine A derivative [DMDA-PatA] treatment at 1 M for 1 h) eIF2␣ phosphorylation (12,13). When cells were stimulated with SA, an oxidative stress stimulus, along with other markers of SGs, SAMD9 nucleated into the SGs (Fig.…”

RNA helicases in infection and disease

“…156 Importantly, pateamine A is not transported by Phosphoglycoprotein, a transporter responsible for multi-drug resistance. 236 Pateamine A leads to an increase in ATPase and helicase activities of eIF4A, but inhibits translation initiation irreversibly. 237,238 It also induces dimerization of eIF4A, 237,239 an increase in RNA affinity 237 and stabilizes the eIF4A/B complex.…”