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The combination of methylsulfonylmethane and tamoxifen inhibits the Jak2/STAT5b pathway and synergistically inhibits tumor growth and metastasis in ER-positive breast cancer xenografts.

S P N, Darvin P, Yoo YB, Joung YH, Kang DY, Kim DN, Hwang TS, Kim SY, Kim WS, Lee HK, Cho BW, Kim HS, Park KD, Park JH, Chang SH, Yang YM - BMC Cancer (2015)

Bottom Line: In the current study, we analyzed the combinatorial effect of MSM and tamoxifen on the suppression of ER-positive breast cancer xenograft growth and metastasis.The intragastric administration of MSM and subcutaneous implantation of tamoxifen tablets led to tumor growth suppression and inhibition of the Janus kinase 2 (Jak2)/signal transducer and activator of transcription 5b (STAT5b) pathway.Therefore, this drug combination may have a synergistic and powerful anticancer effect against breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, School of Medicine, and Institute of Biomedical Science and Technology, Konkuk University, Seoul, 143-701, Korea. nipinsp@gmail.com.

ABSTRACT

Background: Combination therapy, which reduces the dosage intensity of the individual drugs while increasing their efficacy, is not a novel approach for the treatment of cancer. Methylsulfonylmethane (MSM) is an organic sulfur compound shown to act against tumor cells. Tamoxifen is a commercially available therapeutic agent for breast malignancies.

Methods: In the current study, we analyzed the combinatorial effect of MSM and tamoxifen on the suppression of ER-positive breast cancer xenograft growth and metastasis. Additionally, we also validated the molecular targets by which the drug combination regulated tumor growth and metastasis.

Results: We observed that the combination of MSM and tamoxifen regulated cell viability and migration in vitro. The intragastric administration of MSM and subcutaneous implantation of tamoxifen tablets led to tumor growth suppression and inhibition of the Janus kinase 2 (Jak2)/signal transducer and activator of transcription 5b (STAT5b) pathway. Our study also assessed the regulation of signaling molecules implicated in the growth, progression, differentiation, and migration of cancer cells, such as Jak2, STAT5b, insulin-like growth factor-1Rβ, and their phosphorylation status.

Conclusions: Study results indicated that this combination therapy inhibited tumor growth and metastasis. Therefore, this drug combination may have a synergistic and powerful anticancer effect against breast cancer.

No MeSH data available.


Related in: MedlinePlus

The combination of MSM and Tam synergistically inhibited invasion through STAT5b. (a) A Matrigel invasion assay showing the invasion inhibition of Tam, MSM, and the drug combination for 24 h in MCF-7 cells. (b) Graphical representation of the invasion assay results. (c) On-target inhibition of STAT5b inhibited the invasion in T47D cells. (d) Graphical representation of the relative inhibition of invasion after silencing of STAT5b. Statistical analyses were conducted using the ANOVA test (**P < 0.01 and ***P < 0.001)
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Fig4: The combination of MSM and Tam synergistically inhibited invasion through STAT5b. (a) A Matrigel invasion assay showing the invasion inhibition of Tam, MSM, and the drug combination for 24 h in MCF-7 cells. (b) Graphical representation of the invasion assay results. (c) On-target inhibition of STAT5b inhibited the invasion in T47D cells. (d) Graphical representation of the relative inhibition of invasion after silencing of STAT5b. Statistical analyses were conducted using the ANOVA test (**P < 0.01 and ***P < 0.001)

Mentions: The inhibition of invasion was studied using a Matrigel invasion assay (Fig. 4a). A relatively high level of invasion inhibition was observed in combination-treated cells as compared to those treated with the individual drug concentrations (Fig. 4b, P < 0.01 and P < 0.001). In order to determine the role of STAT5b in invasion, we silenced STAT5b using specific siSTAT5b in T47D cells. Following the silencing of STAT5b, we analyzed the invasion using a Matrigel invasion assay. The obtained result provided strong proof for the role of STAT5b in invasion (Fig. 4c). The use of non-target siRNA showed similar expression levels to those from non-siRNA treated controls. Silenced STAT5b showed a significant invasion inhibition as compared with the non-target group (Fig. 4d). Inhibition of cell migration was determined by an in vitro wound healing assay (Fig. 5a). The area of wound closure was quantified using ImageJ software25, and the relative inhibition of migration was determined. The results showed a statistically significant inhibition of migration in the combination-treated cells (Fig. 5b, P < 0.05 and P < 0.01). MMPs are the major mediators of invasion via digestion of the extracellular membrane, which allows for cancer cells to enter the circulation [37]. Hence, an inhibition in MMP expression should lead to the inhibition of invasion. Our drug combination exerted a synergistic inhibition of MMP2, MMP3, and MMP9 at both the transcriptional and translational levels (Fig. 5c and e). Densitometric analysis of MMPs proved the capability of our drug combination to inhibit invasion (Fig. 5d and f).Fig. 4


The combination of methylsulfonylmethane and tamoxifen inhibits the Jak2/STAT5b pathway and synergistically inhibits tumor growth and metastasis in ER-positive breast cancer xenografts.

S P N, Darvin P, Yoo YB, Joung YH, Kang DY, Kim DN, Hwang TS, Kim SY, Kim WS, Lee HK, Cho BW, Kim HS, Park KD, Park JH, Chang SH, Yang YM - BMC Cancer (2015)

The combination of MSM and Tam synergistically inhibited invasion through STAT5b. (a) A Matrigel invasion assay showing the invasion inhibition of Tam, MSM, and the drug combination for 24 h in MCF-7 cells. (b) Graphical representation of the invasion assay results. (c) On-target inhibition of STAT5b inhibited the invasion in T47D cells. (d) Graphical representation of the relative inhibition of invasion after silencing of STAT5b. Statistical analyses were conducted using the ANOVA test (**P < 0.01 and ***P < 0.001)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4472404&req=5

Fig4: The combination of MSM and Tam synergistically inhibited invasion through STAT5b. (a) A Matrigel invasion assay showing the invasion inhibition of Tam, MSM, and the drug combination for 24 h in MCF-7 cells. (b) Graphical representation of the invasion assay results. (c) On-target inhibition of STAT5b inhibited the invasion in T47D cells. (d) Graphical representation of the relative inhibition of invasion after silencing of STAT5b. Statistical analyses were conducted using the ANOVA test (**P < 0.01 and ***P < 0.001)
Mentions: The inhibition of invasion was studied using a Matrigel invasion assay (Fig. 4a). A relatively high level of invasion inhibition was observed in combination-treated cells as compared to those treated with the individual drug concentrations (Fig. 4b, P < 0.01 and P < 0.001). In order to determine the role of STAT5b in invasion, we silenced STAT5b using specific siSTAT5b in T47D cells. Following the silencing of STAT5b, we analyzed the invasion using a Matrigel invasion assay. The obtained result provided strong proof for the role of STAT5b in invasion (Fig. 4c). The use of non-target siRNA showed similar expression levels to those from non-siRNA treated controls. Silenced STAT5b showed a significant invasion inhibition as compared with the non-target group (Fig. 4d). Inhibition of cell migration was determined by an in vitro wound healing assay (Fig. 5a). The area of wound closure was quantified using ImageJ software25, and the relative inhibition of migration was determined. The results showed a statistically significant inhibition of migration in the combination-treated cells (Fig. 5b, P < 0.05 and P < 0.01). MMPs are the major mediators of invasion via digestion of the extracellular membrane, which allows for cancer cells to enter the circulation [37]. Hence, an inhibition in MMP expression should lead to the inhibition of invasion. Our drug combination exerted a synergistic inhibition of MMP2, MMP3, and MMP9 at both the transcriptional and translational levels (Fig. 5c and e). Densitometric analysis of MMPs proved the capability of our drug combination to inhibit invasion (Fig. 5d and f).Fig. 4

Bottom Line: In the current study, we analyzed the combinatorial effect of MSM and tamoxifen on the suppression of ER-positive breast cancer xenograft growth and metastasis.The intragastric administration of MSM and subcutaneous implantation of tamoxifen tablets led to tumor growth suppression and inhibition of the Janus kinase 2 (Jak2)/signal transducer and activator of transcription 5b (STAT5b) pathway.Therefore, this drug combination may have a synergistic and powerful anticancer effect against breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, School of Medicine, and Institute of Biomedical Science and Technology, Konkuk University, Seoul, 143-701, Korea. nipinsp@gmail.com.

ABSTRACT

Background: Combination therapy, which reduces the dosage intensity of the individual drugs while increasing their efficacy, is not a novel approach for the treatment of cancer. Methylsulfonylmethane (MSM) is an organic sulfur compound shown to act against tumor cells. Tamoxifen is a commercially available therapeutic agent for breast malignancies.

Methods: In the current study, we analyzed the combinatorial effect of MSM and tamoxifen on the suppression of ER-positive breast cancer xenograft growth and metastasis. Additionally, we also validated the molecular targets by which the drug combination regulated tumor growth and metastasis.

Results: We observed that the combination of MSM and tamoxifen regulated cell viability and migration in vitro. The intragastric administration of MSM and subcutaneous implantation of tamoxifen tablets led to tumor growth suppression and inhibition of the Janus kinase 2 (Jak2)/signal transducer and activator of transcription 5b (STAT5b) pathway. Our study also assessed the regulation of signaling molecules implicated in the growth, progression, differentiation, and migration of cancer cells, such as Jak2, STAT5b, insulin-like growth factor-1Rβ, and their phosphorylation status.

Conclusions: Study results indicated that this combination therapy inhibited tumor growth and metastasis. Therefore, this drug combination may have a synergistic and powerful anticancer effect against breast cancer.

No MeSH data available.


Related in: MedlinePlus