Inhibitory effect and mechanism of Yishen Qutong granules on bone metastasis of breast cancer in mice
Objective To observe the inhibitory effect of intragastric administration of Yishen Qutong granules(YSQTG)on breast cancer bone metastasis in mice,and to explore its possible mechanism of action.Methods Eighty-four female BABL/c mice were randomly divided into seven groups,with 12 mice in each group.Mice in the model group,ML-385 group,and low,medium,and high dose groups were all implanted with the bone-affine breast cancer high meta-static cell line 4T1.2 cell suspension in the left tibia to create the breast cancer bone metastasis models.On the first day af-ter implantation,mice in the low,medium,and high dose groups were given YSQTG aqueous solution at 2.275,4.55,and 9.1 g/kg,respectively,by gavage,followed by intraperitoneal injection of normal saline.Mice in the ML-385 group were given distilled water by gavage and intraperitoneal injection of nuclear factor E2-related factor 2(Nrf2)inhibitor ML-385(20 mg/kg)dissolved in normal saline.Mice in the blank group,sham operation group,and model group were given equal volume of distilled water by gavage and intraperitoneal injection of normal saline.The dose was administered once a day,for 28 consecutive days.The body weight of mice in each group was recorded from 1 to 4 weeks after treatment,and after 28 days of continuous administration,the mice were sacrificed and the tumor mass was weighed.The left tibia of mice in each group was harvested,and after micro-CT scanning,the bone volume fraction(BV/TV),trabecular thickness(Tb.Th),trabecular number(Tb.N),and trabecular space(Tb.Sp)of cancellous and cortical bone were analyzed.Histopath-ological conditions were observed after HE staining,and the number of osteoclasts and the length of contact surface between osteoclasts and bone tissues were analyzed after tartrate acid phosphatase staining.Immunohistochemical method was used to detect the positive expression rates of Kelch-like ECH-associated protein 1(Keap1)and Nrf2 proteins.Results During the 1 to 4 weeks of treatment,the body weight of mice in each group showed a continuous upward trend.At the 4th week of treatment,the body weight of the model group was lower than that of the other groups(all P<0.05).Compared with the model group,the tumor mass decreased,but only significant difference was found between the ML-385 group and the medi-um dose group(P<0.05).The histopathological examination of the left tibia in the blank group and the sham operation group was normal.In the model group,significant bone metastasis was observed on the left tibia,with the main cellular components of osteogenic bone metastasis.In the ML-385 group and the medium dose group,the formation of bone metas-tasis and the degree of bone destruction on the left tibia were less severe in comparison with those of the model group,while the low and high dose groups were similar to the model group.Compared with the blank group and the sham operation group,the BV/TV,Tb.N,Tb.Sp,Tb.Th,osteoclast numbers,osteoclast contact surface length,and the positive ex-pression rates of Keap1 and Nrf2 in the left tibia tissues of the model group increased(all P<0.05);compared with the model group,the BV/TV,Tb.N,Tb.Sp,Tb.Th,and the positive expression rates of Keap1 and Nrf2 in the left tibia tis-sues of the ML-385 group decreased,the Tb.N,Tb.Sp,and Tb.Th in the left tibia tissue of the medium dose group de-creased,the Tb.Th decreased in the low and high dose groups,and the numbers of osteoclasts,the length of osteoclast contact surfaces,and the positive expression rate of Nrf2 in the left tibia tissues decreased,while the positive expression rate of Keap1 increased in the low,medium,and high dose groups(all P<0.05).Conclusions Intragastric administra-tion of YSQTG can inhibit the growth of bone metastatic tumors and bone destruction in mice with breast cancer,with the medium dose showing the best effect.The mechanism may be related to the regulation of the Keap1/Nrf2 signaling pathway and the reduction of oxidative stress.
breast carcinomabone metastasisYishen Qutong granulesosteoclastsKelch-like ECH-associated protein 1nuclear factor E2-related factor 2
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