TY - JOUR
T1 - Droserone and dioncoquinone B, and related naphthoquinones as potent antiausterity agents against human PANC-1 pancreatic cancer cells
AU - Maneenet, Juthamart
AU - Tajuddeen, Nasir
AU - Hong Nguyen, Hung
AU - Fujii, Rintaro
AU - Kimbadi Lombe, Blaise
AU - Feineis, Doris
AU - Awale, Suresh
AU - Bringmann, Gerhard
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/1
Y1 - 2024/1
N2 - Pancreatic cancer is a highly aggressive disease with a poor prognosis. Its tumor microenvironment is characterized by severe nutrient deprivation and hypoxia, leading to the activation of adaptive pathways that allow cancer cells to survive and thrive under these harsh conditions. This makes conventional therapies less effective, highlighting the urgent need for novel treatment strategies. Naphthoquinones have recently emerged as promising anti-austerity agents, demonstrating preferential cytotoxicity against pancreatic cancer cells in nutrient-deprived medium (NDM). To further explore their potential, we investigated the structure–activity relationships and mechanism of action of a library of 28 natural and synthetic naphthoquinones. Our results reveal a significant influence of functional groups at positions C-2, C-3, C-5, and C-6 on anticancer activity. Strong electron-donating substituents at C-3 decreased the activity, while electron-withdrawing groups at C-3 and H-bond acceptors at C-6 (without H-bond donor activity) increased the potency. The naphthoate esters 4 and 5 exhibited the strongest activity against PANC-1 cells, with PC50 values of 0.87 and 0.42 μM, respectively. These compounds significantly altered cancer cell morphology, induced apoptosis, and inhibited colony formation. Further investigation revealed that compound 5 downregulated the expression of Akt and p-Akt(S473) proteins, suggesting that its anti-austerity activity might involve suppression of the Akt signaling pathway. These findings demonstrate the immense potential of naphthoquinones as novel anticancer agents targeting the austerity-adapted pancreatic cancer cells. Further development of these promising compounds holds significant potential for treating this devastating disease.
AB - Pancreatic cancer is a highly aggressive disease with a poor prognosis. Its tumor microenvironment is characterized by severe nutrient deprivation and hypoxia, leading to the activation of adaptive pathways that allow cancer cells to survive and thrive under these harsh conditions. This makes conventional therapies less effective, highlighting the urgent need for novel treatment strategies. Naphthoquinones have recently emerged as promising anti-austerity agents, demonstrating preferential cytotoxicity against pancreatic cancer cells in nutrient-deprived medium (NDM). To further explore their potential, we investigated the structure–activity relationships and mechanism of action of a library of 28 natural and synthetic naphthoquinones. Our results reveal a significant influence of functional groups at positions C-2, C-3, C-5, and C-6 on anticancer activity. Strong electron-donating substituents at C-3 decreased the activity, while electron-withdrawing groups at C-3 and H-bond acceptors at C-6 (without H-bond donor activity) increased the potency. The naphthoate esters 4 and 5 exhibited the strongest activity against PANC-1 cells, with PC50 values of 0.87 and 0.42 μM, respectively. These compounds significantly altered cancer cell morphology, induced apoptosis, and inhibited colony formation. Further investigation revealed that compound 5 downregulated the expression of Akt and p-Akt(S473) proteins, suggesting that its anti-austerity activity might involve suppression of the Akt signaling pathway. These findings demonstrate the immense potential of naphthoquinones as novel anticancer agents targeting the austerity-adapted pancreatic cancer cells. Further development of these promising compounds holds significant potential for treating this devastating disease.
KW - Antiausterity activity
KW - Droserone
KW - Naphthoquinones
KW - PANC-1
KW - Pancreatic cancer
KW - Structure-activity relationships
UR - http://www.scopus.com/inward/record.url?scp=85184771506&partnerID=8YFLogxK
U2 - 10.1016/j.rechem.2024.101352
DO - 10.1016/j.rechem.2024.101352
M3 - 学術論文
AN - SCOPUS:85184771506
SN - 2211-7156
VL - 7
JO - Results in Chemistry
JF - Results in Chemistry
M1 - 101352
ER -