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Antitumor Actions of Intratumoral Delivery of Membrane-Fused Mitochondria in a Mouse Model of Triple-Negative Breast Cancers.
Onco Targets Ther. 2020; 13:5241-5255.OT

Abstract

Background

The transfer of whole mitochondria has been demonstrated to be beneficial for treating breast cancer because it induces apoptosis and drug sensitivity; however, in vivo evidence of this benefit remains scant. The present study compared the transplantation of mitochondria with instinctive (Mito) and membrane-fused morphologies induced by Pep-1 conjugation (P-Mito) using a mouse model of triple-negative breast cancers.

Materials and Methods

Mice with advanced severe immunodeficiency received orthotopic implantation of MDA-MB-231 human breast cancer cells followed by transplants of 5-bromo-2'-deoxyuridine (BrdU)-labeled Mito or P-Mito (200 μg [10 μg/μL]) through intratumoral injection at multiple points once a week for 4 weeks.

Results

After 1 month of consecutive treatment, 8.2% and 14.2% of the BrdU-labeled mitochondria were preserved in tumors of the Mito and P-Mito groups, respectively. Both Pep-1 and P-Mito treatments reduced tumor weight (21.7% ± 2.43% vs 40.6% ± 2.28%) and led to marked inhibition of Ki67 staining and angiogenesis. However, only the P-Mito group exhibited obvious necrosis and DNA fragmentation accompanied by an altered tumor microenvironment, which included reduced oxidative stress and size of cancer-associated fibroblast populations and enhanced immune cell infiltration. Transmission electron microscopy images further revealed an elongated network of perinuclear mitochondria fused with a few peripheral mitochondria in the nonnecrotic area in the P-Mito group as well as increases in mitochondrial fusion proteins and parkin compared with mitochondrial fission proteins.

Conclusion

In this study, the results of mitochondrial transplantation emphasized that the facilitation of mitochondrial fusion is a critical regulator in breast cancer therapy.

Authors+Show Affiliations

Vascular and Genomic Center, Changhua Christian Hospital, Changhua 50094, Taiwan.Vascular and Genomic Center, Changhua Christian Hospital, Changhua 50094, Taiwan.Department of Medicine, College of Medicine, China Medical University, Taichung 40447, Taiwan.Vascular and Genomic Center, Changhua Christian Hospital, Changhua 50094, Taiwan.Vascular and Genomic Center, Changhua Christian Hospital, Changhua 50094, Taiwan.Vascular and Genomic Center, Changhua Christian Hospital, Changhua 50094, Taiwan.Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua 50094, Taiwan. Department of Medical Research, Changhua Christian Hospital, Changhua 50094, Taiwan.Vascular and Genomic Center, Changhua Christian Hospital, Changhua 50094, Taiwan. Department of Neurology, Changhua Christian Hospital, Changhua 50094, Taiwan. School of Chinese Medicine, Graduate Institute of Chinese Medicine, Graduate Institute of Integrated Medicine, College of Chinese Medicine, Research Center for Chinese Medicine and Acupuncture, China Medical University, Taichung 40447, Taiwan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32606744

Citation

Chang, Jui-Chih, et al. "Antitumor Actions of Intratumoral Delivery of Membrane-Fused Mitochondria in a Mouse Model of Triple-Negative Breast Cancers." OncoTargets and Therapy, vol. 13, 2020, pp. 5241-5255.
Chang JC, Chang HS, Wu YC, et al. Antitumor Actions of Intratumoral Delivery of Membrane-Fused Mitochondria in a Mouse Model of Triple-Negative Breast Cancers. Onco Targets Ther. 2020;13:5241-5255.
Chang, J. C., Chang, H. S., Wu, Y. C., Cheng, W. L., Lin, T. T., Chang, H. J., Chen, S. T., & Liu, C. S. (2020). Antitumor Actions of Intratumoral Delivery of Membrane-Fused Mitochondria in a Mouse Model of Triple-Negative Breast Cancers. OncoTargets and Therapy, 13, 5241-5255. https://doi.org/10.2147/OTT.S238143
Chang JC, et al. Antitumor Actions of Intratumoral Delivery of Membrane-Fused Mitochondria in a Mouse Model of Triple-Negative Breast Cancers. Onco Targets Ther. 2020;13:5241-5255. PubMed PMID: 32606744.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antitumor Actions of Intratumoral Delivery of Membrane-Fused Mitochondria in a Mouse Model of Triple-Negative Breast Cancers. AU - Chang,Jui-Chih, AU - Chang,Huei-Shin, AU - Wu,Yao-Chung, AU - Cheng,Wen-Ling, AU - Lin,Ta-Tsung, AU - Chang,Hui-Ju, AU - Chen,Shou-Tung, AU - Liu,Chin-San, Y1 - 2020/06/09/ PY - 2019/11/11/received PY - 2020/04/23/accepted PY - 2020/7/2/entrez PY - 2020/7/2/pubmed PY - 2020/7/2/medline KW - MDA-MB-231 KW - Pep-1 KW - animal model of breast cancer KW - mitochondrial fusion KW - mitochondrial transplantation KW - tumor growth SP - 5241 EP - 5255 JF - OncoTargets and therapy JO - Onco Targets Ther VL - 13 N2 - Background: The transfer of whole mitochondria has been demonstrated to be beneficial for treating breast cancer because it induces apoptosis and drug sensitivity; however, in vivo evidence of this benefit remains scant. The present study compared the transplantation of mitochondria with instinctive (Mito) and membrane-fused morphologies induced by Pep-1 conjugation (P-Mito) using a mouse model of triple-negative breast cancers. Materials and Methods: Mice with advanced severe immunodeficiency received orthotopic implantation of MDA-MB-231 human breast cancer cells followed by transplants of 5-bromo-2'-deoxyuridine (BrdU)-labeled Mito or P-Mito (200 μg [10 μg/μL]) through intratumoral injection at multiple points once a week for 4 weeks. Results: After 1 month of consecutive treatment, 8.2% and 14.2% of the BrdU-labeled mitochondria were preserved in tumors of the Mito and P-Mito groups, respectively. Both Pep-1 and P-Mito treatments reduced tumor weight (21.7% ± 2.43% vs 40.6% ± 2.28%) and led to marked inhibition of Ki67 staining and angiogenesis. However, only the P-Mito group exhibited obvious necrosis and DNA fragmentation accompanied by an altered tumor microenvironment, which included reduced oxidative stress and size of cancer-associated fibroblast populations and enhanced immune cell infiltration. Transmission electron microscopy images further revealed an elongated network of perinuclear mitochondria fused with a few peripheral mitochondria in the nonnecrotic area in the P-Mito group as well as increases in mitochondrial fusion proteins and parkin compared with mitochondrial fission proteins. Conclusion: In this study, the results of mitochondrial transplantation emphasized that the facilitation of mitochondrial fusion is a critical regulator in breast cancer therapy. SN - 1178-6930 UR - https://www.unboundmedicine.com/medline/citation/32606744/Antitumor_Actions_of_Intratumoral_Delivery_of_Membrane-Fused_Mitochondria_in_a_Mouse_Model_of_Triple-Negative_Breast_Cancers L2 - https://dx.doi.org/10.2147/OTT.S238143 DB - PRIME DP - Unbound Medicine ER -
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