Breast cancer is the most common cancer in females with extremely high lethality mainly due to the occurrence of metastasis,which is closely related to cancer stem-like cells(CSCs).It has been reported that CSC freque...Breast cancer is the most common cancer in females with extremely high lethality mainly due to the occurrence of metastasis,which is closely related to cancer stem-like cells(CSCs).It has been reported that CSC frequency in drug-resistant breast cancer and non-small cell lung cancer is reduced by activating dopamine D1 receptor(D1 DR).In the present study,we aimed to investigate the effect of a compound C17 that can be used orally for breast cancer metastasis as well as the underlying mechanism involving the activation of D1 DR.The confocal immunofluorescence analysis demonstrated that D1 DR was up-regulated by C17.The cell survival and colony formation were inhibited by C17 through the detection by Sulforhodamine B colorimetric(SRB)assay and colony formation assay,respectively.Results from both wound healing assay and transwell assay demonstrated that C17 inhibited the migration of 4T1 cells.Flow cytometry analysis indicated that C17 significantly reduced the CSC frequency.In addition,C17 could inhibit the lung metastasis in 4T1 orthotopic mouse model of breast cancer without obvious toxicity,and it could up-regulate the expression of intratumoral E-cadherin and down-regulate the expressions of Snail and N-cadherin in primary breast tumor,which might be related to the activation of D1 DR.Our findings provided a potential candidate compound for the treatment of metastatic breast cancer with good compliance and safety.展开更多
Breast cancer is the second leading cause of cancer death in women mainly due to metastasis,which is closely related to cancer stemness.Evidence has shown that cancer stem-like cells(CSCs),which are responsible for ca...Breast cancer is the second leading cause of cancer death in women mainly due to metastasis,which is closely related to cancer stemness.Evidence has shown that cancer stem-like cells(CSCs),which are responsible for cancer stemness,can be decreased by activating dopamine D1 receptor(D1 DR).In the present study,we aimed to explore the pharmacological effects as well as the underlying mechanisms of QAP21,a newly synthesized compound that can be orally administered,in metastatic breast cancer cells.Our results showed that QAP21 dose-dependently inhibited the ability of colony formation in 4 T1 and MDA-MB-231 cells.Cell mobility,including cell migration and invasion,was also remarkably inhibited.Besides,QAP21 significantly inhibited mammosphere formation and decreased CSC proportion,indicating reduced cancer stemness.We further verified that the nuclear factor-kappa B(NF-κB)/Akt/epithelial-mesenchymal transition(EMT)pathway was markedly impacted by QAP21 treatment.Moreover,QAP21 up-regulated the expressions of D1 DR and its second messengers,including cAMP and cGMP,which can be increased when D1 DR is activated.SCH 23390,a specific D1 DR antagonist,partially or completely reversed the above-mentioned effects of QAP21,indicating that D1 DR activation might be involved in the underlying mechanism of QAP21.In summary,QAP21 effectively reduced breast cancer stemness and cell mobility,indicating its potential use for metastatic breast cancer therapy.展开更多
Cancer metastasis is a process with multi-step complexity and apparent randomness. In this study, we aimed to establish a stochastic mathematical model to describe the random process of cancer metastasis and predict t...Cancer metastasis is a process with multi-step complexity and apparent randomness. In this study, we aimed to establish a stochastic mathematical model to describe the random process of cancer metastasis and predict the drug effect of QAP14 on metastasis in a mouse model. The data of lung metastases on the 22^(nd) day after cancer cell implantation with or without the treatment of QAP14, a new chemical compound, were collected in 4T1 breast cancer BALB/c mice. Based on the exponential growth of the primary tumor and metastatic loci, a joint distribution model of metastasis size and number was developed. Disease progression of metastasis and preclinical efficacy of QAP14 were modeled. Parameters M and m representing maximum and minimum of metastasis volume were 3.24 and 0.0184 mm^(3), respectively. The metastasis growth rate γ and metastasis promotion time ρ were estimated and fixed to be 0.0216 d^(-1) and 7.8 d, respectively. The efficacy of QAP14 acted on metastasis promotion time and metastasis growth rate constant in an exponential term, and the effect parameter Effectρ and Effectγ were 16.6 and 0.327 g/mg, respectively. In the present study, we comprehensively characterized the random process of lung metastasis and efficacy of QAP14 in 4T1 breast cancer mice, which might provide a useful reference for the establishment of a clinical population model of cancer metastasis.展开更多
基金Beijing Municipal Natural Science Foundation(Grant No.7192100)Innovation Team of Ministry of Education(Grant No.BMU2017TD003)
文摘Breast cancer is the most common cancer in females with extremely high lethality mainly due to the occurrence of metastasis,which is closely related to cancer stem-like cells(CSCs).It has been reported that CSC frequency in drug-resistant breast cancer and non-small cell lung cancer is reduced by activating dopamine D1 receptor(D1 DR).In the present study,we aimed to investigate the effect of a compound C17 that can be used orally for breast cancer metastasis as well as the underlying mechanism involving the activation of D1 DR.The confocal immunofluorescence analysis demonstrated that D1 DR was up-regulated by C17.The cell survival and colony formation were inhibited by C17 through the detection by Sulforhodamine B colorimetric(SRB)assay and colony formation assay,respectively.Results from both wound healing assay and transwell assay demonstrated that C17 inhibited the migration of 4T1 cells.Flow cytometry analysis indicated that C17 significantly reduced the CSC frequency.In addition,C17 could inhibit the lung metastasis in 4T1 orthotopic mouse model of breast cancer without obvious toxicity,and it could up-regulate the expression of intratumoral E-cadherin and down-regulate the expressions of Snail and N-cadherin in primary breast tumor,which might be related to the activation of D1 DR.Our findings provided a potential candidate compound for the treatment of metastatic breast cancer with good compliance and safety.
基金Beijing Municipal Natural Science Foundation(Grant No.7192100)Innovation Team of Ministry of Education(Grant No.BMU2017TD003)。
文摘Breast cancer is the second leading cause of cancer death in women mainly due to metastasis,which is closely related to cancer stemness.Evidence has shown that cancer stem-like cells(CSCs),which are responsible for cancer stemness,can be decreased by activating dopamine D1 receptor(D1 DR).In the present study,we aimed to explore the pharmacological effects as well as the underlying mechanisms of QAP21,a newly synthesized compound that can be orally administered,in metastatic breast cancer cells.Our results showed that QAP21 dose-dependently inhibited the ability of colony formation in 4 T1 and MDA-MB-231 cells.Cell mobility,including cell migration and invasion,was also remarkably inhibited.Besides,QAP21 significantly inhibited mammosphere formation and decreased CSC proportion,indicating reduced cancer stemness.We further verified that the nuclear factor-kappa B(NF-κB)/Akt/epithelial-mesenchymal transition(EMT)pathway was markedly impacted by QAP21 treatment.Moreover,QAP21 up-regulated the expressions of D1 DR and its second messengers,including cAMP and cGMP,which can be increased when D1 DR is activated.SCH 23390,a specific D1 DR antagonist,partially or completely reversed the above-mentioned effects of QAP21,indicating that D1 DR activation might be involved in the underlying mechanism of QAP21.In summary,QAP21 effectively reduced breast cancer stemness and cell mobility,indicating its potential use for metastatic breast cancer therapy.
基金Natural Science Foundation of Beijing Municipality (Grant No. 7192100)。
文摘Cancer metastasis is a process with multi-step complexity and apparent randomness. In this study, we aimed to establish a stochastic mathematical model to describe the random process of cancer metastasis and predict the drug effect of QAP14 on metastasis in a mouse model. The data of lung metastases on the 22^(nd) day after cancer cell implantation with or without the treatment of QAP14, a new chemical compound, were collected in 4T1 breast cancer BALB/c mice. Based on the exponential growth of the primary tumor and metastatic loci, a joint distribution model of metastasis size and number was developed. Disease progression of metastasis and preclinical efficacy of QAP14 were modeled. Parameters M and m representing maximum and minimum of metastasis volume were 3.24 and 0.0184 mm^(3), respectively. The metastasis growth rate γ and metastasis promotion time ρ were estimated and fixed to be 0.0216 d^(-1) and 7.8 d, respectively. The efficacy of QAP14 acted on metastasis promotion time and metastasis growth rate constant in an exponential term, and the effect parameter Effectρ and Effectγ were 16.6 and 0.327 g/mg, respectively. In the present study, we comprehensively characterized the random process of lung metastasis and efficacy of QAP14 in 4T1 breast cancer mice, which might provide a useful reference for the establishment of a clinical population model of cancer metastasis.
