Nicolaioidesin C: An Antiausterity Agent Shows Promising Antitumor Activity in a Pancreatic Cancer Xenograft Mouse Model

Human pancreatic tumors are hypovascular in nature, and
their tumor
microenvironment is often characterized by hypoxia and severe nutrient
deprivation due to uncontrolled heterogeneous growth, a phenomenon
known as “austerity”. However, pancreatic tumor cells
have the inherent ability to adapt and thrive even in such low nutrient
and hypoxic microenvironments. Anticancer drugs such as gemcitabine
and paclitaxel, which target rapidly proliferating cells, are often
ineffective against nutrient-deprived pancreatic cancer cells. In
order to overcome this limitation, the search for novel agents that
can eliminate cancer cells’ adaptations to nutrition starvation,
also known as “antiausterity” agents, represents a promising
strategy to make the cancer cells susceptible to treatment. The natural
product (+)-nicolaioidesin C (Nic-C) was found to have potent antiausterity
activity against the PANC-1 human pancreatic cancer cell line in a
nutrient-deprived condition. However, its efficacy in vivo remained untested. To address this, we synthesized Nic-C in its
racemic form and evaluated its antitumor potential in a human pancreatic
cancer xenograft model. Nic-C inhibited pancreatic cancer cell migration
and colony formation and significantly inhibited tumor growth in MIA
PaCa-2 xenografts in a dose-dependent manner. Furthermore, Nic-C inhibited
the Akt/mTOR and autophagy signaling pathways in both in vitro and in vivo studies. Metabolomic profiling of in vivo tumor samples suggests that Nic-C downregulates
amino acid metabolism while upregulating sphingolipid metabolism.