Details

Autor(en) / Beteiligte

• Awale, Suresh
• Baba, Hayato
• Phan, Nguyen Duy
• Kim, Min Jo
• Maneenet, Juthamart
• Sawaki, Koichi
• Kanda, Mitsuro
• Okumura, Tomoyuki
• Fujii, Tsutomu
• Okada, Takuya
• Maruyama, Takahiro
• Okada, Takahiro
• Toyooka, Naoki

Titel

Targeting Pancreatic Cancer with Novel Plumbagin Derivatives: Design, Synthesis, Molecular Mechanism, In Vitro and In Vivo Evaluation

Ist Teil von

• Journal of medicinal chemistry, 2023-06, Vol.66 (12), p.8054-8065

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2023

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Pancreatic tumors grow in an “austerity” tumor microenvironment characterized by nutrient deprivation and hypoxia. This leads to the activation of adaptive pathways in pancreatic cancer cells, promoting tolerance to nutrition starvation and aggressive malignancy. Conventional anticancer drugs are often ineffective against tumors that grow in such austerity condition. Plumbagin, a plant-derived naphthoquinone, has shown potent preferential cytotoxicity against pancreatic cancer cells under nutrient-deprived conditions. Therefore, we synthesized a series of plumbagin derivatives and found that 2-(cyclohexylmethyl)-plumbagin (3f) was the most promising compound with a PC50 value of 0.11 μM. Mechanistically, 3f was found to inhibit the PI3K/Akt/mTOR signaling pathways, leading to cancer cell death under nutrient-deprived conditions. In vivo studies using pancreatic cancer xenograft mouse models confirmed the efficacy of 3f, demonstrating significant inhibition of tumor growth in a dose-dependent manner. Compound 3f represents a highly promising lead for anticancer drug development based on an antiausterity strategy.