title: Thymoquinone reduces mouse colon tumor cell invasion and inhibits tumor growth in murine colon cancer models.
abstract: We have shown that thymoquinone (TQ) is a potent antitumor agent in human colorectal cancer cells. In this study, we evaluated TQ's therapeutic potential in two different mice colon cancer models [1,2-dimethyl hydrazine (DMH) and xenografts]. We also examined TQ effects on the growth of C26 mouse colorectal carcinoma spheroids and assessed tumor invasion in vitro. Mice were treated with saline, TQ, DMH, or combinations once per week for 30 weeks and the multiplicity, size and distribution of aberrant crypt foci (ACF) and tumors were determined at weeks 10, 20 and 30. TQ injected intraperitoneally (i.p.) significantly reduced the numbers and sizes of ACF at week 10; ACF numbers were reduced by 86%. Tumor multiplicity was reduced at week 20 from 17.8 in the DMH group to 4.2 in mice injected with TQ. This suppression was observed at week 30 and was long-term; tumors did not re-grow even when TQ injection was discontinued for 10 weeks. In a xenograft model of HCT116 colon cancer cells, TQ significantly (P < 0.05) delayed the growth of the tumor cells. Using a matrigel artificial basement membrane invasion assay, we demonstrated that sub-cyto-toxic doses of TQ (40 microM) decreased C26 cell invasion by 50% and suppressed growth in three-dimensional spheroids. Apoptotic signs seen morphologically were increased significantly in TQ-treated spheroids. TUNEL staining of xenografts and immunostaining for caspase 3 cleavage in DMH tumors confirmed increased apoptosis in mouse tumors in response to TQ. These data should encourage further in vivo testing and support the potential use of TQ as a therapeutic agent in human colorectal cancer.
authors: Department of Biology, American University of Beirut, Beirut, Lebanon. amro@aub.edu.lb
authors: Hala
authors: H
authors: Gali-Muhtasib
authors: Matthias
authors: M
authors: Ocker
authors: Doerthe
authors: D
authors: Kuester
authors: Sabine
authors: S
authors: Krueger
authors: Zeina
authors: Z
authors: El-Hajj
authors: Antje
authors: A
authors: Diestel
authors: Matthias
authors: M
authors: Evert
authors: Nahed
authors: N
authors: El-Najjar
authors: Brigitte
authors: B
authors: Peters
authors: Abdo
authors: A
authors: Jurjus
authors: Albert
authors: A
authors: Roessner
authors: Regine
authors: R
authors: Schneider-Stock
mesh_terms: D019813:1,2-Dimethylhydrazine; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D018874:Spheroids, Cellular; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; C505409:Casp3 protein, mouse; D053148:Caspase 3; D019813:1,2-Dimethylhydrazine; C003466:thymoquinone