scholarly journals Indocyanine Green-Parthenolide Thermosensitive Liposome Combination Treatment for Triple-Negative Breast Cancer

2020 ◽  
Vol Volume 15 ◽  
pp. 3193-3206
Author(s):  
Xin Jin ◽  
Xinyue Lu ◽  
Zhenhai Zhang ◽  
Huixia Lv
Keyword(s):  
Breast Cancer ◽  
Indocyanine Green ◽  
Triple Negative Breast Cancer ◽  
Combination Treatment ◽  
Triple Negative ◽  
Thermosensitive Liposome

scholarly journals CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer

2021 ◽  
Vol 22 (11) ◽  
pp. 5782
Author(s):  
Ashwini Makhale ◽  
Devathri Nanayakkara ◽  
Prahlad Raninga ◽  
Kum Kum Khanna ◽  
Murugan Kalimutho
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Triple Negative Breast Cancer ◽  
Combination Treatment ◽  
Triple Negative ◽  
Annexin V ◽  
Replication Stress ◽  
Breast Cancer Cell Lines ◽  
Combination Strategy

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapy. Here, we evaluated the anti-cancer activity of APR-246, a P53 activator, and CX-5461, a RNA polymerase I inhibitor, in the treatment of TNBC cells. We tested the efficacy of individual and combination therapy of CX-5461 and APR-246 in vitro, using a panel of breast cancer cell lines. Using publicly available breast cancer datasets, we found that components of RNA Pol I are predominately upregulated in basal-like breast cancer, compared to other subtypes, and this upregulation is associated with poor overall and relapse-free survival. Notably, we found that the treatment of breast cancer cells lines with CX-5461 significantly hampered cell proliferation and synergistically enhanced the efficacy of APR-246. The combination treatment significantly induced apoptosis that is associated with cleaved PARP and Caspase 3 along with Annexin V positivity. Likewise, we also found that combination treatment significantly induced DNA damage and replication stress in these cells. Our data provide a novel combination strategy by utilizing APR-246 in combination CX-5461 in killing TNBC cells that can be further developed into more effective therapy in TNBC therapeutic armamentarium.

Wee1 Inhibition Enhances the Anti-Tumor Effects of Capecitabine in Preclinical Models of Triple-Negative Breast Cancer.

2020 ◽  
Author(s):  
Todd Pitts ◽  
Dennis M Simmons ◽  
Stacey M Bagby ◽  
Sarah J Hartman ◽  
Betelehem W Yacob ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Combination Treatment ◽  
Triple Negative ◽  
Single Agent ◽  
Cell Analysis ◽  
Preclinical Models ◽  
Pdx Models ◽  
Live Cell Analysis

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive subtype defined by lack of hormone receptor expression and non-amplified HER2. Adavosertib (AZD1775) is a potent, small molecule, ATP-competitive inhibitor of the Wee1 kinase that potentiates the activity of many DNA-damaging chemotherapeutics and is currently in clinical development for multiple indications. The purpose of this study was to investigate the combination of AZD1775 and capecitabine/5-FU in preclinical TNBC models. Methods: TNBC cell lines were treated with AZD1775 and 5-FU and cellular proliferation was assessed in real-time using IncuCyte® Live Cell Analysis. Apoptosis was assessed via the Caspase-Glo 3/7 assay system. Western blotting was used to assess changes in expression of downstream effectors. TNBC PDX models were treated with AZD1775, capecitabine, or the combination and assessed for tumor growth inhibition. Results: From the initial PDX screen, two of the four TNBC PDX models demonstrated a better response in the combination treatment than either of the single agents. As confirmation, two PDX models were expanded for statistical comparison . Both PDX models demonstrated a significant growth inhibition in the combination versus either of the single agents. (TNBC012, p<0.05 combo vs adavosertib or capecitabine, TNBC013, p<0.01 combo vs adavosertib or capecitabine ). An enhanced antiproliferative effect was observed in the adavosertib/5-FU combination treatment as measured by live cell analysis. An increase in apoptosis was observed in two of the four cell lines in the combination when compared to single agent treatment. Treatment with single agent adavosertib resulted in an increase in p-CDC2 in a dose dependent manner that was also observed in the combination treatment. Similar results were observed with γH2AX in two of the four cell lines tested. No significant changes were observed in Bcl-xL following treatment in any of the cell lines. Conclusions: The combination of adavosertib and capecitabine/5-FU demonstrated enhanced combination effects both in vitro and in vivo in preclinical models of TNBC. These results support the clinical investigation of this combination in patients with TNBC, including those with brain metastasis given the CNS penetration of both agents.

scholarly journals A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1703
Author(s):  
Hui-Wen Chiu ◽  
Ya-Ling Yeh ◽  
Sheng-Yow Ho ◽  
Yuan-Hua Wu ◽  
Bour-Jr Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Aggregation ◽  
Er Stress ◽  
Histone Deacetylase ◽  
Triple Negative Breast Cancer ◽  
Combination Treatment ◽  
Histone Deacetylase Inhibitors ◽  
Triple Negative ◽  
Combined Treatment ◽  
Misfolded Protein

Radiation therapy (RT) is one of the main treatments for triple-negative breast cancer (TNBC). However, many patients experience RT failure due to the metastatic potential of RT and the radiation resistance of several cancers. Histone deacetylase inhibitors (HDACis) can serve as radiosensitizers. In this study, we investigated whether a novel HDACi, TMU-35435, could reinforce radiosensitivity through the induction of misfolded protein aggregation and autophagy in TNBC. Significantly enhanced toxicity was found for the combination treatment compared with TMU-35435 or irradiation (IR) treatment alone in TNBC cells. The combination treatment induced misfolded protein aggregation and TMU-35435 inhibited the interaction of HDAC6 with dynein. Furthermore, the combined treatment induced endoplasmic reticulum (ER) stress but did not trigger apoptosis. In addition, the combination treatment caused autophagic cell death. Tumor growth in the mouse of model orthotopic breast cancer was suppressed by the combination treatment through the induction of ER stress and autophagy. These findings support the future evaluation of the novel HDACi TMU-35435, as a potent radiosensitizer in TNBC.

scholarly journals OSW-1 Induces Apoptosis and Cyto-Protective Autophagy, and Synergizes with Doxorubicin on Spontaneous Metastasis of Triple Negative Breast Cancer

2021 ◽  
Author(s):  
Mengling Wu ◽  
Huizhi Xi ◽  
Mengya Liao ◽  
Hongbo Ma ◽  
Shanrui Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Combination Treatment ◽  
Natural Compound ◽  
Triple Negative ◽  
Synergistic Effects ◽  
Underlying Mechanism ◽  
Spontaneous Metastasis

Abstract Background Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer and chemotherapy using drugs such as doxorubicin is the main treatment strategy. However, drug resistance and dose-dependent toxicities restricted its clinical use. Natural products are major sources of anti-tumor drugs. OSW-1 is a natural compound that has shown strong anti-cancer effects in several cancer types, but its effects on the efficacies of chemotherapy in TNBC and the underlying mechanism remain unclear. Methods We investigated the effects of OSW-1 on the viabilities, apoptosis and autophagy in 4T1 and MDA-MB-231 cells. The synergistic effects of combination with OSW-1 and doxorubicin on TNBC growth and spontaneous metastasis were examined in vitro and in vivo. Results OSW-1 induces mitochondria-dependent apoptosis and cyto-protective autophagy in TNBC cells in vitro. In addition, OSW-1 and doxorubicin exhibits strong synergistic anti-TNBC capabilities both in vivo and in vitro. The combination treatment can strongly inhibit spontaneous metastasis in 4T1 model. Consistent with this inhibition, the proportion of CD8+ T lymphocytes in the lung microenvironment were significantly increased after combination treatment. Conclusions This study indicates that the combination therapy with natural compound and chemotherapeutic drug could be a promising anti-TNBC strategy which deserves further investigation.

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