Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived xenograft (PDX) model

Abstract

Despite the significant progress in the field of cancer therapeutics, the incidence of pancreatic cancer (PC) has continuously increased. One possible mechanism for this increasing burden is impaired drug delivery and drug resistance resulting from a unique tumor microenvironment and genetic mutations. Apratoxins are potent anticancer agents and cotranslational translocation inhibitors with potential therapeutic applications to treat cancers with active secretory pathways. Here, we developed apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent which potently inhibited the growth of both established and patient-derived primary pancreatic cancer cells. We validated its mechanism of action on pancreatic cancer cells by demonstrating the downregulation of multiple receptor tyrosine kinases and inhibition of growth factor and cytokine secretion. Apra S10 also inhibited a number of cytokines secreted by stromal cells, suggesting that Apra S10 not only inhibited pancreatic cancer cell secretion, but also reduced the level of factors secreted by other cell types active within the tumor microenvironment. As Apra S10 tissue distribution indicated its high enrichment in pancreas tissue, an orthotopic pancreatic patient-derived xenograft mouse model that closely mimics the human pancreatic tumor microenvironment was for the first time used in apratoxin studies. Apra S10 showed promising antitumor effect in this pancreatic cancer model and this effect was mediated through anti-proliferation properties.

Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases

“…Apratoxins were previously reported to exert its function by inhibiting protein co-translational translocation at the level of Sec61 translocon, leading to downregulation of various receptor tyrosine kinases and growth factors. 13,14,[16][17][18]36 Consistent with these observations [20], receptor tyrosine kinase VEGFR2 and VEGFR3 expressions were significantly inhibited in Apratoxin S4-treated HRECs. Similarly, receptor tyrosine kinase PDGFR-b level in HRPCs was also suppressed by Apratoxin S4.…”

“…Natural and synthetic Apratoxins are potent antitumor and antiangiogenic macrocyclic depsipeptides derived from marine cyanobacteria. [16][17][18]35,36 It was reported that Apratoxins exert their function through inhibiting co-translational translocation of secreted or membrane bound proteins, 13 which may offer an alternative way to control the activation of angiogenic pathways.…”

Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds

“…Sandra Ramos-Inza 1,2 , Carlos Aydillo 1,2 , Carmen Sanmartín 1,2 and Daniel Plano 1,2 * 1 Faculty of Pharmacy and Nutrition, Department of Pharmaceutical Technology and Chemistry, University of Navarra, Pamplona, Spain 2 Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain *Address all correspondence to: dplano@alumni.unav.es (R)-C 30 thiazoline and the addition of a methyl group at C 34 , shows potent in vitro angiogenesis and vascularized tumor cell growth inhibition [93]. It showed antipancreatic cancer activity, including in orthotopic pancreatic patient-derived xenograft mouse model [94]. Other derivatizations consisting of thiazoline substitution by piperidinecarboxylic acid moiety have been developed [95].…”

<p>Enhancement of Antitumor Efficacy of Paclitaxel-Loaded PEGylated Liposomes by N,N-Dimethyl Tertiary Amino Moiety in Pancreatic Cancer</p>

“…The PDOX models of PDAC were established as described previously. 33 – 35 Once acquired from the specimen, the tumor was cut into fragments of approximately 3mm 3 to transplant subcutaneously into NOD/SCID mice as the first generation. Then, the nude mice were implanted with the patient tumor growing in NOD/SCID mice as the second generation to establish the models.…”