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Thymoquinone reduces mouse colon tumor cell invasion and inhibits tumor growth in murine colon cancer models.

Gali-Muhtasib H, Ocker M, Kuester D, Krueger S, El-Hajj Z, Diestel A, Evert M, El-Najjar N, Peters B, Jurjus A, Roessner A, Schneider-Stock R - J. Cell. Mol. Med. (2008 Jan-Feb)

Bottom Line: TQ injected intraperitoneally (i.p.) significantly reduced the numbers and sizes of ACF at week 10; ACF numbers were reduced by 86%.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, American University of Beirut, Beirut, Lebanon. amro@aub.edu.lb

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.

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Histology of the HCT116 xenograft tumors upon staining with H&E, Ki-67 and TUNEL: (A, B) Hematoxylin and Eosin staining of xenograft tumors. The proliferation index determined by Ki-67 staining showed no significant difference between the TQ-treated xenografts (D) and the untreated control (C). An increased apoptotic index measured by TUNEL was observed in the TQ-treated xenograft (F) as compared to the untreated control (E). (Zeiss Axioscope 50, camera:Nikon Coolpix 990; x200).
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fig04: Histology of the HCT116 xenograft tumors upon staining with H&E, Ki-67 and TUNEL: (A, B) Hematoxylin and Eosin staining of xenograft tumors. The proliferation index determined by Ki-67 staining showed no significant difference between the TQ-treated xenografts (D) and the untreated control (C). An increased apoptotic index measured by TUNEL was observed in the TQ-treated xenograft (F) as compared to the untreated control (E). (Zeiss Axioscope 50, camera:Nikon Coolpix 990; x200).

Mentions: The macroscopically observed growth delay was not due to reduced proliferation of tumor cells as evidenced by MIB1 staining (Fig. 4). Staining showed that the proliferation index of tumors of untreated controls (87.9%) was similar to that of the TQ-treated xenografts (86.7%) (Fig. 4C and D). On the other hand, TQ treatment lead to increased TUNEL positivity (Fig. 4E and F), indicating that, in this model as well, the diminished tumor size in TQ-treated xenografts was mainly due to the induction of cell death. In the TQ-treated group, median apoptotic index estimated by TUNEL was 3.8% as compared to 2.4% in vehicle controls.


Thymoquinone reduces mouse colon tumor cell invasion and inhibits tumor growth in murine colon cancer models.

Gali-Muhtasib H, Ocker M, Kuester D, Krueger S, El-Hajj Z, Diestel A, Evert M, El-Najjar N, Peters B, Jurjus A, Roessner A, Schneider-Stock R - J. Cell. Mol. Med. (2008 Jan-Feb)

Histology of the HCT116 xenograft tumors upon staining with H&E, Ki-67 and TUNEL: (A, B) Hematoxylin and Eosin staining of xenograft tumors. The proliferation index determined by Ki-67 staining showed no significant difference between the TQ-treated xenografts (D) and the untreated control (C). An increased apoptotic index measured by TUNEL was observed in the TQ-treated xenograft (F) as compared to the untreated control (E). (Zeiss Axioscope 50, camera:Nikon Coolpix 990; x200).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3823493&req=5

fig04: Histology of the HCT116 xenograft tumors upon staining with H&E, Ki-67 and TUNEL: (A, B) Hematoxylin and Eosin staining of xenograft tumors. The proliferation index determined by Ki-67 staining showed no significant difference between the TQ-treated xenografts (D) and the untreated control (C). An increased apoptotic index measured by TUNEL was observed in the TQ-treated xenograft (F) as compared to the untreated control (E). (Zeiss Axioscope 50, camera:Nikon Coolpix 990; x200).
Mentions: The macroscopically observed growth delay was not due to reduced proliferation of tumor cells as evidenced by MIB1 staining (Fig. 4). Staining showed that the proliferation index of tumors of untreated controls (87.9%) was similar to that of the TQ-treated xenografts (86.7%) (Fig. 4C and D). On the other hand, TQ treatment lead to increased TUNEL positivity (Fig. 4E and F), indicating that, in this model as well, the diminished tumor size in TQ-treated xenografts was mainly due to the induction of cell death. In the TQ-treated group, median apoptotic index estimated by TUNEL was 3.8% as compared to 2.4% in vehicle controls.

Bottom Line: TQ injected intraperitoneally (i.p.) significantly reduced the numbers and sizes of ACF at week 10; ACF numbers were reduced by 86%.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, American University of Beirut, Beirut, Lebanon. amro@aub.edu.lb

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.

Show MeSH
Related in: MedlinePlus