Abstract:PurposeThe exact mechanism regulating fibronectin (FN) expression in breast cancer cells has not been fully elucidated. In this study, we investigated the pharmacological mechanism of berberine (BBR) with respect to FN expression in triple-negative breast cancer (TNBC) cells.MethodsThe clinical significance of FN mRNA expression was analyzed using the Kaplan-Meier plotter database (http://kmplot.com/breast). FN mRNA and protein expression levels were analyzed by real-time polymerase chain reaction and western … Show more
“…For the individual cancer types, the top ovarian cancer cell selective inhibitor was fostamatinib [35] (IC 50 = 6.24 ± 4.06 μM; SI >100), a Syk kinase inhibitor (Supplementary Figure 8 A - D and Table 3). The top placental cancer line inhibitor was berberine [36], [37] (IC 50 = 4.41 ± 0.662 μM; SI >100), an anti-parasitic alkaloid targeting Complex I of the mitochondrial respiratory chain and AP-1 machinery (Supplementary Figure 8 E - H and Table 3). The cervical cancer selective inhibitory compounds found in our study were also active for the ovarian cancer cells.Figure 2Chemotherapeutic diversity in cell line killing.…”
Heterogeneous response to chemotherapy is a major issue for the treatment of cancer. For most gynecologic cancers including ovarian, cervical, and placental, the list of available small molecule therapies is relatively small compared to options for other cancers. While overall cancer mortality rates have decreased in the United States as early diagnoses and cancer therapies have become more effective, ovarian cancer still has low survival rates due to the lack of effective treatment options, drug resistance, and late diagnosis. To understand chemotherapeutic diversity in gynecologic cancers, we have screened 7914 approved drugs and bioactive compounds in 11 gynecologic cancer cell lines to profile their chemotherapeutic sensitivity. We identified two HDAC inhibitors, mocetinostat and entinostat, as pan-gynecologic cancer suppressors with IC50 values within an order of magnitude of their human plasma concentrations. In addition, many active compounds identified, including the non-anticancer drugs and other compounds, diversely inhibited the growth of three gynecologic cancer cell groups and individual cancer cell lines. These newly identified compounds are valuable for further studies of new therapeutics development, synergistic drug combinations, and new target identification for gynecologic cancers. The results also provide a rationale for the personalized chemotherapeutic testing of anticancer drugs in treatment of gynecologic cancer.
“…For the individual cancer types, the top ovarian cancer cell selective inhibitor was fostamatinib [35] (IC 50 = 6.24 ± 4.06 μM; SI >100), a Syk kinase inhibitor (Supplementary Figure 8 A - D and Table 3). The top placental cancer line inhibitor was berberine [36], [37] (IC 50 = 4.41 ± 0.662 μM; SI >100), an anti-parasitic alkaloid targeting Complex I of the mitochondrial respiratory chain and AP-1 machinery (Supplementary Figure 8 E - H and Table 3). The cervical cancer selective inhibitory compounds found in our study were also active for the ovarian cancer cells.Figure 2Chemotherapeutic diversity in cell line killing.…”
Heterogeneous response to chemotherapy is a major issue for the treatment of cancer. For most gynecologic cancers including ovarian, cervical, and placental, the list of available small molecule therapies is relatively small compared to options for other cancers. While overall cancer mortality rates have decreased in the United States as early diagnoses and cancer therapies have become more effective, ovarian cancer still has low survival rates due to the lack of effective treatment options, drug resistance, and late diagnosis. To understand chemotherapeutic diversity in gynecologic cancers, we have screened 7914 approved drugs and bioactive compounds in 11 gynecologic cancer cell lines to profile their chemotherapeutic sensitivity. We identified two HDAC inhibitors, mocetinostat and entinostat, as pan-gynecologic cancer suppressors with IC50 values within an order of magnitude of their human plasma concentrations. In addition, many active compounds identified, including the non-anticancer drugs and other compounds, diversely inhibited the growth of three gynecologic cancer cell groups and individual cancer cell lines. These newly identified compounds are valuable for further studies of new therapeutics development, synergistic drug combinations, and new target identification for gynecologic cancers. The results also provide a rationale for the personalized chemotherapeutic testing of anticancer drugs in treatment of gynecologic cancer.
“…BBR is known to be a low-toxicity and safe agent and was reported to have multiple biological functions, including antimicrobial, anti-inflammatory, and antitumor effects [4,5,6,7,8,9,10,11,12,13]. Treatment with 13-EBR, a BBR analog that is substituted at C-13 by alkyl groups, was reported to have anti-inflammatory effects [16,17]; however, the role of this molecule in tumor suppression was not reported.…”
Section: Discussionmentioning
confidence: 99%
“…Berberine (BBR) is an isoquinoline alkaloid that is isolated from Cotridis rhizoma and has multiple biological activities, such as antimicrobial, anti-inflammatory, and antitumor effects [4,5,6,7]. In particular, the anticancer effects of BBR on breast cancer cells were reported; BBR induces breast cancer cell apoptosis via the activation of the apoptotic signaling pathway [8,9], the inhibition of proliferation and migration [10], the suppression of cell motility through the downregulation of related molecules [11,12], and the enhancement of chemosensitivity, which induces apoptosis [13]. Recently, it was reported that 13-alkyl-substituted berberines showed better antimicrobial activity against certain bacterial species and cytotoxic activity against human cancer cell lines than BBR [14,15].…”
Berberine is reported to have multiple biological effects, including antimicrobial, anti-inflammatory, and antitumor activities, and 13-alkyl-substituted berberines show higher activity than berberine against certain bacterial species and human cancer cell lines. In particular, 13-ethylberberine (13-EBR) was reported to have anti-inflammatory effects in endotoxin-activated macrophage and septic mouse models. Thus, in this study, we aimed to examine the anticancer effects of 13-EBR and its mechanisms in radiotherapy-resistant (RT-R) MDA-MB-231 cells derived from the highly metastatic MDA-MB-231 cells. When we compared the gene expression between MDA-MB-231 and RT-R MDA-MB-231 cells with an RNA microarray, RT-R MDA-MB-231 showed higher levels of anti-apoptotic genes and lower levels of pro-apoptotic genes compared to MDA-MB-231 cells. Accordingly, we examined the effect of 13-EBR on the induction of apoptosis in RT-R MDA-MB-231 and MDA-MB-231 cells. The results showed that 13-EBR reduced the proliferation and colony-forming ability of both MDA-MB-231 and RT-R MDA-MB-231 cells. Moreover, 13-EBR induced apoptosis by promoting both intracellular and mitochondrial reactive oxygen species (ROS) and by regulating the apoptosis-related proteins involved in the intrinsic pathway, not in the extrinsic pathway. These results suggest that 13-EBR has pro-apoptotic effects in RT-R MDA-MB-231 and MDA-MB-231 cells by inducing mitochondrial ROS production and activating the mitochondrial apoptotic pathway, providing useful insights into new potential therapeutic strategies for RT-R breast cancer treatment.
“…The tumor-suppressor protein TP53 is a transcription factor that regulates anti-carcinogenesis programs associated with apoptosis, cell cycle arrest, and DNA repair in genotoxic and not-genotoxic cellular injuries (32,33). In recent studies, we reported that the level of fibronectin expression is associated with the status and expression of TP53 in breast cancer cells (34,35). Wu et al reported that Slug is transcriptionally induced by TP53 and then escapes from apoptosis by repressing the TP53-mediated transcription of Puma (36).…”
In a previous study, we reported that α-smooth muscle actin (α-SMA), one of the mesenchymal marker proteins, is highly expressed in tamoxifen-resistant breast cancer (TamR) cells. However, the exact mechanism of α-SMA expression in TamR cells is not fully understood. Here, we investigated the effect of TP53 on α-SMA expression in breast cancer cells. The levels of α-SMA mRNA and protein expression were analyzed by real-time PCR and western blotting, respectively. In estrogen receptor-positive [ER(+)] breast cancer patients, aberrant α-SMA expression was found to be associated with a poor prognosis. The level of α-SMA expression was significantly increased in established TamR cells compared to tamoxifen-sensitive (TamS) cells. To verify the regulatory mechanism of α-SMA expression, we analyzed diverse kinase activities between TamS and TamR cells. The activity of TP53 was markedly increased in the TamR cells. When TamS cells were treated with TP53 activator, Nutlin3 (Nut3), α-SMA expression was increased in the TamS cells. In addition, α-SMA expression was significantly increased by TP53 overexpression in breast cancer cells. On the contrary, the basal level of α-SMA expression was decreased by the TP53 inhibitor, pifithrin-α (PFT-α). Taken together, we demonstrated that α-SMA expression is regulated by TP53 activity in TamR cells.
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