Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: April 12, 2022

Abstract Triple-negative breast cancer (TNBC) is a subtype of human with one the worst prognoses, no targeted therapeutic strategies currently available. Regulated cell death (RCD), also known as programmed (PCD), has been widely reported to have numerous links progression and therapy many types cancer. Of note, RCD can be divided into different subroutines, including autophagy-dependent death, apoptosis, mitotic catastrophe, necroptosis, ferroptosis, pyroptosis anoikis. More recently, targeting subroutines small-molecule compounds emerging promising strategy, which rapidly progressed in treatment TNBC. Therefore, this review, we focus on summarizing molecular mechanisms above-mentioned seven major related TNBC latest progress subroutines. Moreover, further discuss combined drug (e.g., narciclasine) or more drugs torin-1 chloroquine) achieve potential by regulating importantly, demonstrate several ONC201 NCT03733119) clinical trials. Taken together, these findings will provide clue illuminating actionable low-hanging-fruit druggable targets candidate for RCD-related therapies. Graphical abstract

Language: Английский

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Unveiling the connection: Long-chain non-coding RNAs and critical signaling pathways in breast cancer

Pathology - Research and Practice, Journal Year: 2023, Volume and Issue: 249, P. 154736 - 154736

Published: Aug. 3, 2023

Language: Английский

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Current Molecular Combination Therapies Used for the Treatment of Breast Cancer

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(19), P. 11046 - 11046

Published: Sept. 20, 2022

Breast cancer is the second leading cause of death for women worldwide. While monotherapy (single agent) treatments have been used many years, they are not always effective, and patients relapse after initial treatment. Moreover, in some response to therapy becomes weaker, or resistance develops over time. This especially problematic metastatic breast triple-negative cancer. Recently, combination therapies (in which two more drugs target pathways) emerged as promising new treatment options. Combination often effective than monotherapies demonstrate lower levels toxicity during long-term In this review, we provide a comprehensive overview current therapies, including molecular-targeted therapy, hormone immunotherapy, chemotherapy. We also describe molecular basis various options different subtypes. promising, discuss challenges. Despite these challenges, use innovative holds great promise compared with traditional monotherapies. addition, multidisciplinary technologies (such nanotechnology computer technology) has potential optimize even further.

Language: Английский

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Inhibition of autophagy by chloroquine prevents resistance to PI3K/AKT inhibitors and potentiates their antitumor effect in combination with paclitaxel in triple negative breast cancer models

Journal of Translational Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: June 27, 2022

Abstract Background Triple negative breast cancer (TNBC) is an aggressive disease characterized by high risk of relapse and development resistance to different chemotherapy agents. Several targeted therapies have been investigated in TNBC with modest results clinical trials. Among these, PI3K/AKT inhibitors evaluated addition standard therapies, yielding conflicting making attempts on elucidating inherent mechanisms great interest. Increasing evidences suggest that can induce autophagy cancers. Autophagy represents a supposed mechanism drug-resistance tumors, like TNBC. We, therefore, if two inhibitors, ipatasertib taselisib, could models, whether chloroquine (CQ), well known inhibitor, potentiate taselisib anti-cancer effect combination conventional chemotherapy. Methods The induction after treatment was MDAMB231, MDAM468, MCF7, SKBR3 MDAB361 cell lines assaying LC3-I conversion LC3-II through immunoblotting immunofluorescence. Other autophagy-markers as p62/SQSTM1 ATG5 were immunoblotting. Synergistic antiproliferative double triple combinations ipatasertib/taselisib plus CQ and/or paclitaxel SRB assay clonogenic assay. Anti-apoptotic increased cleaved-PARP immunoblot Annexin V- flow cytometric analysis. In vivo experiments performed xenograft model MDAMB231 NOD/SCID mice. Results Our suggested signaling models. This particularly evident resistant cells, where the inhibition potentiates therapeutic vitro synergizing taxane-based Conclusion These data authophagy overcome drug evaluation such trials warranted.

Language: Английский

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Role of Medicinal plant‐derived Nutraceuticals as a potential target for the treatment of breast cancer

Journal of Food Biochemistry, Journal Year: 2022, Volume and Issue: 46(12)

Published: Sept. 19, 2022

Breast cancer (BC) is one of the most challenging cancers to treat, accounting for many cancer-related deaths. Over some years, chemotherapy, hormone treatment, radiation, and surgeries have been used treat cancer. Unfortunately, these treatment options are unsuccessful due crucial adverse reactions multidrug tolerance/resistance. Although it clear that substances in nutraceuticals category a lot anti-cancer activity, using supplementary therapy strategy, this case, could be very beneficial. Nutraceuticals therapeutic agents, which nutrients drug-like characteristics can diseases. Plant categorized into polyphenols, terpenoids, vitamins, alkaloids, flavonoids part health food products, great potential combating BC. reduce BC's severity, limit malignant cell growth, modify mechanisms. acting by attenuating Hedgehog, Nuclear factor kappa-light-chain-enhancer activated B cells (NF-κB), Notch, Wnt/β-catenin signaling main pathways controlling self-renewal breast stem (BCSCs). This article reviews important their modes action, powerful versus Practical applications Nutraceuticals' importance control diagnosis undeniable cannot overlooked. Natural dietary compounds wide range uses traditional medicine. In addition, natural chemicals enhance effectiveness other medicines. They may also as process independently because capacity affect several pathways. study highlights variety chemicals, mechanisms routes, synergistic effects, future potentials all examined.

Language: Английский

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Targeting lncRNA DDIT4‐AS1 Sensitizes Triple Negative Breast Cancer to Chemotherapy via Suppressing of Autophagy

Advanced Science, Journal Year: 2023, Volume and Issue: 10(17)

Published: April 25, 2023

Abstract In this study, it is found that the lncRNA, DNA damage inducible transcript 4 antisense RNA1 (DDIT4‐AS1), highly expressed in triple‐negative breast cancer (TNBC) cell lines and tissues due to H3K27 acetylation promoter region, promotes proliferation, migration, invasion of TNBC cells via activating autophagy. Mechanistically, shown DDIT4‐AS1 induces autophagy by stabilizing DDIT4 mRNA recruiting RNA binding protein AUF1 promoting interaction between AUF1, thereby inhibiting mTOR signaling pathway. Furthermore, silencing enhances sensitivity chemotherapeutic agents such as paclitaxel both vitro vivo. Using a self‐activatable siRNA/drug core–shell nanoparticle system, which effectively deliver siRNA tumor‐bearing mice, significantly enhanced antitumor activity achieved. Importantly, codelivery nanoparticles exert stronger effect on patient‐derived organoids. These findings indicate lncRNA DDIT4‐AS1‐mediated activation progression chemoresistance TNBC, targeting may be exploited new therapeutic approach enhancing efficacy chemotherapy against TNBC.

Language: Английский

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Autophagy and Breast Cancer: Connected in Growth, Progression, and Therapy

Cells, Journal Year: 2023, Volume and Issue: 12(8), P. 1156 - 1156

Published: April 14, 2023

Despite an increase in the incidence of breast cancer worldwide, overall prognosis has been consistently improving owing to development multiple targeted therapies and novel combination regimens including endocrine therapies, aromatase inhibitors, Her2-targeted cdk4/6 inhibitors. Immunotherapy is also being actively examined for some subtypes. This positive outlook marred by resistance or reduced efficacy drug combinations, but underlying mechanisms are somewhat unclear. It interesting note that cells quickly adapt evade most activating autophagy, a catabolic process designed recycle damaged cellular components provide energy. In this review, we discuss role autophagy autophagy-associated proteins growth, sensitivity, tumor dormancy, stemness, recurrence. We further explore how intersects reduces radiotherapy, chemotherapies as well immunotherapy via modulating various intermediate proteins, miRs, lncRNAs. Lastly, potential application inhibitors bioactive molecules improve anticancer effects drugs circumventing cytoprotective discussed.

Language: Английский

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Novel exosomal circEGFR facilitates triple negative breast cancer autophagy via promoting TFEB nuclear trafficking and modulating miR-224-5p/ATG13/ULK1 feedback loop

Oncogene, Journal Year: 2024, Volume and Issue: 43(11), P. 821 - 836

Published: Jan. 27, 2024

Abstract Triple-negative breast cancer (TNBC) cells are in a more hypoxic and starved state than non-TNBC cells, which makes TNBC always maintain high autophagy levels. Emerging evidence has demonstrated that circular RNAs (circRNAs) involved the progress of tumorigenesis. However, regulation functions autophagy-induced circRNAs remain unclear. In our study, autophagy-responsive circRNA candidates under amino acid were identified by RNA sequencing. The results showed circEGFR expression was significantly upregulated autophagic cells. Knockdown inhibited derived from exosomes induced recipient tumor microenvironment. vitro vivo functional assays as an oncogenic TNBC. Clinically, positively associated with lymph node metastasis. CircEGFR plasma-derived patients compared healthy people. Mechanistically, facilitated translocation Annexin A2 (ANXA2) toward plasma membrane led to release Transcription Factor EB (a transcription factor autophagy-related proteins, TFEB) ANXA2-TFEB complex, causing nuclear TFEB, thereby promoting Meanwhile, acted ceRNA directly binding miR-224-5p miR-224-5p, weakened suppressive role miR-224-5p/ATG13/ULK1 axis on autophagy. Overall, study demonstrates key autophagy, malignant progression, metastasis These indicate is potential diagnosis biomarker therapeutic target for

Language: Английский

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The emerging role of noncoding RNAs in the PI3K/AKT/mTOR signalling pathway in breast cancer

Pathology - Research and Practice, Journal Year: 2024, Volume and Issue: 255, P. 155180 - 155180

Published: Jan. 30, 2024

Language: Английский

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The Multifaceted Role of Flavonoids in Cancer Therapy: Leveraging Autophagy with a Double-Edged Sword

Antioxidants, Journal Year: 2021, Volume and Issue: 10(7), P. 1138 - 1138

Published: July 19, 2021

Flavonoids are considered as pleiotropic, safe, and readily obtainable molecules. A large number of recent studies have proposed that flavonoids potential in the treatment tumors by modulation autophagy. In many cases, suppress cancer stimulating excessive autophagy or impairing flux especially apoptosis-resistant cells. However, anti-cancer activity may be attenuated due to simultaneous induction protective Notably, flavonoids-triggered is becoming a trend for preventing clinical setting protecting patients from conventional therapeutic side effects normal tissues. this review, focusing on underlying autophagic mechanisms flavonoids, we hope provide new perspective application therapy. addition, highlight research ideas development dosage forms improve their various pharmacological effects, establishing ideal candidates prevention therapy clinic.

Language: Английский

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