Structure-activity studies on therapeutic potential of Thymoquinone analogs in pancreatic cancer.
OBJECTIVE
Pancreatic cancer (PC) is one of the deadliest of all tumors. Previously, we were the first to show that Thymoquinone (TQ) derived from black seed (Nigella sativa) oil has anti-tumor activity against PC. However, the concentration of TQ required was considered to be high to show this efficacy. Therefore, novel analogs of TQ with lower IC(50) are highly desirable.


METHODS
We have synthesized a series of 27 new analogs of TQ by modifications at the carbonyl sites or the benzenoid sites using single pot synthesis and tested their biological activity in PC cells.


RESULTS
Among these compounds, TQ-2G, TQ-4A1 and TQ-5A1 (patent pending) were found to be more potent than TQ in terms of inhibition of cell growth, induction of apoptosis and modulation of transcription factor-NF-kappaB. We also found that our novel analogs were able to sensitize gemcitabine and oxaliplatin-induced apoptosis in MiaPaCa-2 (gemcitabine resistant) PC cells, which was associated with down-regulation of Bcl-2, Bcl-xL, survivin, XIAP, COX-2 and the associated Prostaglandin E2.


CONCLUSIONS
From our results, we conclude that three of our novel TQ analogs warrant further investigation against PC, especially in combination with conventional chemotherapeutic agents.
Banerjee
Sanjeev
S
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Azmi
Asfar S
AS
Padhye
Subhash
S
Singh
Marjit W
MW
Baruah
Jubaraj B
JB
Philip
Philip A
PA
Sarkar
Fazlul H
FH
Mohammad
Ramzi M
RM
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011458:Prostaglandins E / Q000378:metabolism; D013329:Structure-Activity Relationship; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D016227:Benzoquinones; D016328:NF-kappa B; D009944:Organoplatinum Compounds; D011458:Prostaglandins E; D000077150:Oxaliplatin; D003841:Deoxycytidine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C003466:thymoquinone; D000093542:Gemcitabine