Combination of mitochondria targeting doxorubicin with Bcl-2 function-converting peptide NuBCP-9 for synergistic breast cancer metastasis inhibition

Yang, Jiatao; Li, Qiuyi; Zhou, Minglu; Lin, Xi; Xiang, Yucheng; Xie, Dandan; Huang, Yuan; Zhou, Zhou

doi:10.1039/d0tb02564j

Cited by 8 publications

(6 citation statements)

References 47 publications

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“…Therefore, the stronger the expression of Bcl-2, the higher the malignant degree of the tumor and the worse the biological behaviour of the tumor. Bcl-2, however, has been shown in more and more clinical studies to be associated with some favourable outcomes in breast cancer [12,13]. It was found by Melella et al [14], that estrogen can stimulate the expression of Bcl-2 in MCF-7 cancer cell line, confirming that the expression of Bcl-2 is regulated by estrogen, and the expression of this protein is mostly limited to ER-positive breast cancer cells.…”

Section: Discussionmentioning

confidence: 93%

The significance of Bcl-2 expression in breast cancer: a 10-year follow-up study

Huang¹,

Zhang²,

Wang³

2021

J Clin Invest Stud

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Introduction:To investigate the correlation between the positive expression of Bcl-2 and the clinical characteristics of breast cancer patients.Methods: A total of 124 patients with breast cancer were enrolled in the study. The relationship between the positive expression of Bcl-2 and the clinical characteristics [age, maximum tumor diameter, axillary lymphnode metastasis, clinical stage, histological grade, estrogen receptor (ER), progestogen receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67] in breast cancer patients was analysed. All the patients with 10-year follow-up information were analysed, and the logistic regression analysis and multivariable COX analyses was regression are utilized to screen for risk factors associated with positive Bcl-2 expression. Results:(1) The positive expression rate of Bcl-2 differed significantly among breast cancer patients with different clinical stage and histological grade, while breast cancer patients with different maximum tumor diameter had varied Bcl-2 positive expression rate, with statistical significance (P<0.05); (2) the positive expression rate of Bcl-2 among patients with negative axillary lymph node metastasis was significantly higher than that of those with positive axillary lymph node metastasis (P<0.05); (3) the positive expression rate of Bcl-2 among luminal typle breast cancer patients was significantly higher than that in Tripple negative breast cancer and Her-2 positive breast cancer patients. (P<0.05); (4) Frome the 5-year and 10-year follow-up information of all the patients, Bcl-2 positive breast cancer patients have significantly better prognosis than those of Bcl-2 negative breast cancer patients. With the extension of follow-up time, the prognosis of Bcl-2 positive patients is further improved; (5) Multivariable COX analyses were regression indicated that the independent risk factors for 10 years overall survival were axillary lymph node metastasis, Positive expression of Bcl-2 is a good prognostic factor, but there are not enough data to show that Bcl-2 is an independent risk factor for breast cancer. Conclusion:There was a suggestion of a strong protective effect of Bcl-2 positive expression patients, thus the detection of Bcl-2 is somewhat meaningful value for evaluating the medical conditions and prognosis of breast cancer patients.

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Section: Discussionmentioning

confidence: 93%

The significance of Bcl-2 expression in breast cancer: a 10-year follow-up study

Huang¹,

Zhang²,

Wang³

2021

J Clin Invest Stud

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“…We investigated whether the Bcl-2-dependent apoptosis induced by BFC1103 correlated with a change in the conformation of Bcl-2, converting its function from an antiapoptotic to a proapoptotic protein. − We used a Bcl-2-BH3 domain antibody that specifically recognizes Bcl-2 with a changed conformation. Following treatment with BFC1103, the altered conformation of Bcl-2 was detected in MDA-MB-231/Bcl-2 cells (Figure A).…”

Section: Resultsmentioning

confidence: 99%

“…Nur77 translocates from the nucleus to the mitochondria upon stimulation with certain compounds and initiates apoptosis. − Nur77 interacts with Bcl-2, resulting in mitochondrial localization of Nur77 and induction of apoptosis. We discovered a 9-amino acid Nur77-derived Bcl-2 converting peptide (NuBCP-9), which is capable of mimicking the mechanistic and functional activities of Nur77. − NuBCP-9 binds to the loop domain of Bcl-2, altering its phenotype to a prodeath protein by exposing its BH3 domain. − As with many anticancer compounds, resistance has been reported to small molecule inhibitors of the Bcl-2 family of proteins. − While most therapies are targeted to effectively inhibit primary tumors, there are hardly any reliable therapies for metastatic cancers. Because of this, metastasis accounts for up to 80% of cancer mortality.…”

mentioning

confidence: 99%

Small Molecule Functional Converter of B-Cell Lymphoma-2 (Bcl-2) Suppresses Breast Cancer Lung Metastasis

Kopparapu,

Löhr,

Pearce

et al. 2024

ACS Pharmacol. Transl. Sci.

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The B-cell lymphoma-2 (Bcl-2) family of proteins plays a vital role in tumorigenesis. Cancer cells utilize the expression of Bcl-2 to evade therapy and develop resistance. Bcl-2 overexpression also causes cancer cells to be more invasive and metastatic. About 80% of cancer deaths are due to metastases, and yet targeted therapies for metastatic cancers are scarce. We discovered a small molecule, BFC1103, which changes the conformation of Bcl-2 to convert the antiapoptotic protein to a proapoptotic protein. BFC1103-induced apoptosis is dependent on the expression levels of Bcl-2, with higher levels causing more apoptosis. BFC1103 suppressed the growth of breast cancer lung metastasis. BFC1103 has the potential for further optimization and development for clinical testing in metastatic cancers that express Bcl-2. This study demonstrates a new approach to target Bcl-2 using a small molecule, BFC1103, to suppress metastatic disease.

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“…A Bcl-2-functional conversion peptide (NuBCP9, i.e., N9), derived from the orphan nuclear receptor Nur77, was also used with paclitaxel delivered by polylactic acid–polyethylene glycolpolypropylene glycol–polyethylene glycol [PLA-(PEG-PPG-PEG)] nanoparticles to synergistically treat breast cancer for enhanced therapy efficiency . Yang et al also used hydroxypropyl methacrylamide (HPMA) copolymers to construct a mitochondria-targeting peptide-modified doxorubicin (DOX-MPP) HPMA conjugate and a N9 peptide-loaded HPMA conjugate, respectively, through a pH-sensitive hydrazone bond and reductive environment-responsive disulfide bond for the combined use against metastatic breast cancer, which successfully inhibited 84% of lung metastasis . In our previous research, we also reported a kind of hybrid nanocomposites, which consisted of the internal large pore-sized MSNs and the external PAMAM dendrimers for coloading and sequentially delivering the N9 peptide and DOX to the mitochondria and nucleus for synergistically treating drug-resistant cancers .…”

Section: Introductionmentioning

confidence: 99%

“…6 Yang et al also used hydroxypropyl methacrylamide (HPMA) copolymers to construct a mitochondria-targeting peptide-modified doxorubicin (DOX-MPP) HPMA conjugate and a N9 peptideloaded HPMA conjugate, respectively, through a pH-sensitive hydrazone bond and reductive environment-responsive disulfide bond for the combined use against metastatic breast cancer, which successfully inhibited 84% of lung metastasis. 7 In our previous research, we also reported a kind of hybrid nanocomposites, which consisted of the internal large poresized MSNs and the external PAMAM dendrimers for coloading and sequentially delivering the N9 peptide and DOX to the mitochondria and nucleus for synergistically treating drug-resistant cancers. 8 However, the research on releasing the polypeptide/protein drugs at the targeted sites in a spatiotemporal controlled manner and combination treatment against resistant tumors with a medicinal compound in an enhanced way was rarely reported.…”

Section: Introductionmentioning

confidence: 99%

Acid-Responsive Macroporous Silica Nanoparticles for Bcl-2-Functional-Converting Peptide Release and Synergism with Celastrol for Enhanced Therapy against Resistant Cancer

Zhou

Lin

et al. 2023

ACS Appl. Mater. Interfaces

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Combination of chemotherapeutics with polypeptide/protein drugs has been demonstrated to be an effective approach for treatment against cancer multidrug resistance. However, due to the low biostability and weak cell penetrating ability of biomacromolecules, intracellular delivery and release of biomacromolecules in a spatiotemporally controllable manner in target sites in vivo face great challenges, and synergistic effects will not be achieved as expected just by simple drug combination. Here, we conceived an inspired strategy to combat the drug-resistant tumors by fabricating multiarm PEG-gated large pore-sized mesoporous silica nanoparticles for the Bcl-2-functional-converting peptide (denoted as N9@M-CA∼8P) payload and controlled release and realizing synergistic effects with celastrol integration at a low dosage as a curative sensitizer. Our results demonstrated that the N9 peptide could be pH-responsively released from the macropores of the M-CA∼8P nanosystem both in simulated physiological environments and in cancer cells and at tumor sites. Biosafe and enhanced therapeutic outcomes (90% tumor inhibition) were obtained by combination of the N9@M-CA∼8P nanosystem with celastrol coordinatively inducing mitochondrion-mediated cell apoptosis in resistant cancer cell lines and in the corresponding xenografted mice models. Overall, this study provides convincing evidence for effective and safe resistant cancer treatment through a stimulus-responsive biomacromolecule nanosystem combined with a low dosage of a natural compound.

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Combination of mitochondria targeting doxorubicin with Bcl-2 function-converting peptide NuBCP-9 for synergistic breast cancer metastasis inhibition

Abstract: Distant organ metastasis is the main cause of death in breast cancer patients.

Cited by 8 publications

References 47 publications

The significance of Bcl-2 expression in breast cancer: a 10-year follow-up study

The significance of Bcl-2 expression in breast cancer: a 10-year follow-up study

Small Molecule Functional Converter of B-Cell Lymphoma-2 (Bcl-2) Suppresses Breast Cancer Lung Metastasis

Acid-Responsive Macroporous Silica Nanoparticles for Bcl-2-Functional-Converting Peptide Release and Synergism with Celastrol for Enhanced Therapy against Resistant Cancer

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