Eribulin Synergistically Increases Anti-Tumor Activity of an mTOR Inhibitor by Inhibiting pAKT/pS6K/pS6 in Triple Negative Breast Cancer

Wen, Wei; Marcinkowski, Emily F.; Luyimbazi, David; Luu, Thehang; Xing, Q.; Yan, Jin; Wang, Yujun; Wu, Jun; Guo, Yuming; Tully, Dylan; Han, Ernest; Yost, Susan E.; Yuan, Yuan; Yim, John H.

doi:10.3390/cells8091010

Cited by 25 publications

(18 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This may be a potential mechanism through which paclitaxel shows lower anti-TNBC metastasis capability. Similar results were reported by Wen et al (33).…”

Section: Discussionsupporting

confidence: 92%

“…In addition, we observed that paclitaxel, unlike SSA, increased p-AKT expression in lung tissue and exhibited lower inhibiting efficacy on TNBC lung metastasis than did SSA in the 4T1 mouse model. Wen et al (33) also reported the up-regulation effect of paclitaxel on p-AKT, which suggests a possible mechanism for the relatively poor overall survival of patients with metastatic TNBC treated with paclitaxel (34).…”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Saikosaponin A Inhibits Triple-Negative Breast Cancer Growth and Metastasis Through Downregulation of CXCR4

Wang

Zhao²,

Han

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

Purpose: Due to a lack of recognized molecular targets for therapy, patients with triple-negative breast cancer (TNBC), unlike other subtypes of breast cancers, generally have not benefited from the advances made with targeted agents. The CXCR4/SDF-1 axis is involved in tumor growth and metastasis of TNBC. Therefore, down-regulation of the expression of CXCR4 in cancer cells is a potential therapeutic strategy for inhibiting primary tumor growth and metastasis of TNBC. In order to identify bioactive compounds that inhibit the expression of CXCR4 in traditional Chinese medicines, we investigated the capacity of saikosaponin A (SSA), one of the active ingredients isolated from Radix bupleuri, to affect CXCR4 expression and function in TNBC cells.Methods: Analyses of cell growth, migration, invasion, and protein expression were performed. Knockdowns by small interfering RNA (siRNA) and non-invasive bioluminescence were also used.Results: SSA reduced proliferation and colony formation of SUM149 and MDA-MB-231 cells. SSA inhibited migration and invasion of TNBC cells. For mice, SSA inhibited primary tumor growth and reduced lung metastasis of highly metastatic, triple-negative 4T1-luc cells. SSA inhibited CXCR4 expression but did not regulate CXCR7 expression in vitro and in vivo. The inhibitory effects on the migration and invasion of TNBC cells were reversed by down-regulation of CXCR4 expression. In addition, SSA inactivated the Akt/mTOR signaling pathway and inhibited MMP-9 and MMP-2 expression. Conclusions:The results show that SSA exerts an anti-TNBC effect through the inhibition of CXCR4 expression and thus has the potential to be a candidate therapeutic agent for TNBC patients.

show abstract

“…This may be a potential mechanism through which paclitaxel shows lower anti-TNBC metastasis capability. Similar results were reported by Wen et al (33).…”

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 94%

Saikosaponin A Inhibits Triple-Negative Breast Cancer Growth and Metastasis Through Downregulation of CXCR4

Wang

Zhao²,

Han

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…Targeting the AKT/mTOR pathway has been considered an attractive approach in cancer treatment (Li et al, 2015;Chen et al, 2019b;Wen et al, 2019). PERK and the AKT/mTOR pathway exhibit mutual regulation.…”

Section: Discussionmentioning

confidence: 99%

CCT020312 Inhibits Triple-Negative Breast Cancer Through PERK Pathway-Mediated G1 Phase Cell Cycle Arrest and Apoptosis

Zhou

et al. 2020

Front. Pharmacol.

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) has a poor prognosis due to the lack of specific therapeutic targets. CCT020312, a selective eukaryotic translation initiation factor 2 alpha (eIF2a)/protein kinase RNA-like endoplasmic reticulum kinase (PERK) activator, may have a potent anti-tumor effect. In the present study, we examined the effects of CCT020312 on TNBC and explored the underlying mechanism. We found that CCT020312 inhibited the viability of TNBC cell lines, MDA-MB-453 and CAL-148, by inducing apoptosis and G1 phase cell cycle arrest. CCT020312 decreased the protein levels of cyclin-dependent kinase 4 (CDK4), CDK6, cyclin D1, and B-cell lymphoma 2 (Bcl-2) and increased the levels of Bcl-2-associated X protein (Bax) and cleaved poly (ADP-ribose) polymerase (PARP) compared with those in the control. CCT020312 activated PERK/eIF2a/activating transcription factor 4 (ATF4)/CCAAT-enhancer binding protein (C/EBP) homologous protein transcription factor (CHOP) signaling and inhibited protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) signaling. Furthermore, CCT020312 inhibited tumor growth in an MDA-MB-453 orthotopic xenograft mouse model by activating the PERK/eIF2a/ATF4/CHOP pathway and inhibiting the AKT/mTOR pathway. Thus, our study shows that CCT020312 may be a potential drug candidate for TNBC treatment.

show abstract

“…Tumor samples were fixed in 10% formalin and embedded in paraffin. IHC was performed using VENTANA Ultra IHC automated stainer (VENTANA Medical Systems, Roche Diagnostics, Indianapolis, IN, USA) as described previously [ 66 ]. Slides were scanned with VENTANA iScan HT using VENTANA Image Viewer (VENTANA Medical Systems, Roche Diagnostics, Indianapolis, IN, USA).…”

Section: Methodsmentioning

confidence: 99%

Synergistic Anti-Tumor Activity by Targeting Multiple Signaling Pathways in Ovarian Cancer

Wen

Han

Dellinger

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

More effective therapy is needed to improve the survival of patients with advanced and recurrent ovarian cancer. Preclinical and early clinical studies with single molecular targeted agents have shown limited antitumor activity in ovarian cancer, likely due to compensation by alternative growth/survival pathways. An emerging strategy in overcoming resistance is to combine inhibitors targeting multiple pathways. In this study, we used a novel strategy of combining several FDA-approved targeted drugs, including sunitinib, dasatinib, and everolimus, in human ovarian cancers. Combination of the tyrosine kinase inhibitor sunitinib with the SRC inhibitor dasatinib showed synergistic anti-tumor activity in human ovarian cancer cells. The increased activity was associated with inhibition of the STAT3, SRC, and MAPK signaling pathways, but not AKT signaling. To inhibit the PI3K/AKT/mTOR pathway, we added the mTOR inhibitor everolimus, which further increased anti-tumor activity in cells. Combined treatment with sunitinib, dasatinib, and everolimus also resulted in greater inhibition of human ovarian tumor growth in mice. Furthermore, the triple combination also synergistically increased the anti-tumor activity of paclitaxel, both in vitro and in vivo. Taken together, our results demonstrate that simultaneous inhibition of several signaling pathways results in better anti-tumor activity compared to inhibiting any of these signaling pathways alone.

show abstract

Eribulin Synergistically Increases Anti-Tumor Activity of an mTOR Inhibitor by Inhibiting pAKT/pS6K/pS6 in Triple Negative Breast Cancer

Cited by 25 publications

References 56 publications

Saikosaponin A Inhibits Triple-Negative Breast Cancer Growth and Metastasis Through Downregulation of CXCR4

Saikosaponin A Inhibits Triple-Negative Breast Cancer Growth and Metastasis Through Downregulation of CXCR4

CCT020312 Inhibits Triple-Negative Breast Cancer Through PERK Pathway-Mediated G1 Phase Cell Cycle Arrest and Apoptosis

Synergistic Anti-Tumor Activity by Targeting Multiple Signaling Pathways in Ovarian Cancer

Contact Info

Product

Resources

About