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The apoptotic mechanisms of MT-6, a mitotic arrest inducer, in human ovarian cancer cells

View Article: PubMed Central - PubMed

ABSTRACT

Patients with ovarian cancer are typically diagnosed at an advanced stage, resulting in poor prognosis since there are currently no effective early-detection screening tests for women at average-risk for ovarian cancer. Here, we investigated the effects of MT-6, a derivative of moscatilin, in ovarian cancer cells. Our investigation showed that MT-6 inhibited the proliferation and viability of ovarian cancer cells with submicromolar IC50 values. MT-6–treated SKOV3 cells showed significant cell cycle arrest at G2/M phase, followed by an increase in the proportion of cells in a sub-G1 phase. In addition, MT-6 induced a concentration-dependent increase in mitotic markers, mitotic kinases, cell cycle regulators of G2/M transition, and apoptosis-related markers in ovarian cancer cells. MT-6 treatment also induced mitochondrial membrane potential loss, JNK activation, and DR5 expression. Cotreatment of cells with the JNK inhibitor SP600125 considerably attenuated MT-6–induced apoptosis, mitochondria membrane potential loss, DR5 upregulation, and suppression of cell viability. MT-6 also inhibited tumor growth in an SKOV3 xenograft model without significant body weight loss. Together, our findings suggest that MT-6 is a potent anticancer agent with tumor-suppressive activity in vitro and in vivo that could be further investigated for ovarian cancer therapy in the future.

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MT-6 inhibits tumor growth in SKOV3 xenografted mice.(A) MT-6 reduces tumor volume in an SKOV3 xenograft model. (B) MT-6 treatment did not cause significant loss of body weight in tested animals. Mice bearing established SKOV3 tumors (~100 mm3) were injected intraperitoneally with 5 or 10 mg/kg/d of MT-6 for 50 days, and tumor volumes were measured as described in Materials and Methods (n = 6 mice/group; *P < 0.05 compared with vehicle control). (C) Effects of MT-6 on intratumoral biomarkers in SKOV3 xenograft model. Tumors were harvested at terminal sacrifice and intratumoral proteins of two representatives from each group were collected and subjected to Western blot analysis.
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f8: MT-6 inhibits tumor growth in SKOV3 xenografted mice.(A) MT-6 reduces tumor volume in an SKOV3 xenograft model. (B) MT-6 treatment did not cause significant loss of body weight in tested animals. Mice bearing established SKOV3 tumors (~100 mm3) were injected intraperitoneally with 5 or 10 mg/kg/d of MT-6 for 50 days, and tumor volumes were measured as described in Materials and Methods (n = 6 mice/group; *P < 0.05 compared with vehicle control). (C) Effects of MT-6 on intratumoral biomarkers in SKOV3 xenograft model. Tumors were harvested at terminal sacrifice and intratumoral proteins of two representatives from each group were collected and subjected to Western blot analysis.

Mentions: To extend this analysis in vivo, we treated nude mice bearing established SKOV3 tumors with two different, low doses of MT-6. As shown in Fig. 8A, treatment with MT-6 at a dose of 5 or 10 mg/kg/d inhibited tumor growth by 19.6% and 35.5%, respectively, on day 50 post-treatment compared with vehicle controls. In addition, no adverse body weight loss was observed (Fig. 8B), suggesting that MT-6 treatment is relatively non-toxic. Moreover, intratumoral biomarkers in untreated or MT-6 treated tumors were also analyzed. The data revealed the MT-6 increased the phosphorylation of JNK and DR5 expression, and apoptosis as evidenced by the activation of caspase-3 and PARP (Fig. 8C).


The apoptotic mechanisms of MT-6, a mitotic arrest inducer, in human ovarian cancer cells
MT-6 inhibits tumor growth in SKOV3 xenografted mice.(A) MT-6 reduces tumor volume in an SKOV3 xenograft model. (B) MT-6 treatment did not cause significant loss of body weight in tested animals. Mice bearing established SKOV3 tumors (~100 mm3) were injected intraperitoneally with 5 or 10 mg/kg/d of MT-6 for 50 days, and tumor volumes were measured as described in Materials and Methods (n = 6 mice/group; *P < 0.05 compared with vehicle control). (C) Effects of MT-6 on intratumoral biomarkers in SKOV3 xenograft model. Tumors were harvested at terminal sacrifice and intratumoral proteins of two representatives from each group were collected and subjected to Western blot analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384015&req=5

f8: MT-6 inhibits tumor growth in SKOV3 xenografted mice.(A) MT-6 reduces tumor volume in an SKOV3 xenograft model. (B) MT-6 treatment did not cause significant loss of body weight in tested animals. Mice bearing established SKOV3 tumors (~100 mm3) were injected intraperitoneally with 5 or 10 mg/kg/d of MT-6 for 50 days, and tumor volumes were measured as described in Materials and Methods (n = 6 mice/group; *P < 0.05 compared with vehicle control). (C) Effects of MT-6 on intratumoral biomarkers in SKOV3 xenograft model. Tumors were harvested at terminal sacrifice and intratumoral proteins of two representatives from each group were collected and subjected to Western blot analysis.
Mentions: To extend this analysis in vivo, we treated nude mice bearing established SKOV3 tumors with two different, low doses of MT-6. As shown in Fig. 8A, treatment with MT-6 at a dose of 5 or 10 mg/kg/d inhibited tumor growth by 19.6% and 35.5%, respectively, on day 50 post-treatment compared with vehicle controls. In addition, no adverse body weight loss was observed (Fig. 8B), suggesting that MT-6 treatment is relatively non-toxic. Moreover, intratumoral biomarkers in untreated or MT-6 treated tumors were also analyzed. The data revealed the MT-6 increased the phosphorylation of JNK and DR5 expression, and apoptosis as evidenced by the activation of caspase-3 and PARP (Fig. 8C).

View Article: PubMed Central - PubMed

ABSTRACT

Patients with ovarian cancer are typically diagnosed at an advanced stage, resulting in poor prognosis since there are currently no effective early-detection screening tests for women at average-risk for ovarian cancer. Here, we investigated the effects of MT-6, a derivative of moscatilin, in ovarian cancer cells. Our investigation showed that MT-6 inhibited the proliferation and viability of ovarian cancer cells with submicromolar IC50 values. MT-6&ndash;treated SKOV3 cells showed significant cell cycle arrest at G2/M phase, followed by an increase in the proportion of cells in a sub-G1 phase. In addition, MT-6 induced a concentration-dependent increase in mitotic markers, mitotic kinases, cell cycle regulators of G2/M transition, and apoptosis-related markers in ovarian cancer cells. MT-6 treatment also induced mitochondrial membrane potential loss, JNK activation, and DR5 expression. Cotreatment of cells with the JNK inhibitor SP600125 considerably attenuated MT-6&ndash;induced apoptosis, mitochondria membrane potential loss, DR5 upregulation, and suppression of cell viability. MT-6 also inhibited tumor growth in an SKOV3 xenograft model without significant body weight loss. Together, our findings suggest that MT-6 is a potent anticancer agent with tumor-suppressive activity in vitro and in vivo that could be further investigated for ovarian cancer therapy in the future.

No MeSH data available.


Related in: MedlinePlus