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Novel combinatorial autophagy inhibition therapy for triple negative breast cancers.
Abd El-Aziz, Yomna S; Toit-Thompson, Taymin du; McKay, Matthew J; Molloy, Mark P; Stoner, Shihani; McDowell, Betty; Moon, Elizabeth; Sioson, Loretta; Sheen, Amy; Chou, Angela; Gill, Anthony J; Jansson, Patric J; Sahni, Sumit.
Afiliação
  • Abd El-Aziz YS; Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt.
  • Toit-Thompson TD; Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia.
  • McKay MJ; Kolling Institute of Medical Research, University of Sydney, Australia.
  • Molloy MP; Kolling Institute of Medical Research, University of Sydney, Australia.
  • Stoner S; Kolling Institute of Medical Research, University of Sydney, Australia.
  • McDowell B; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia.
  • Moon E; Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia.
  • Sioson L; Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia.
  • Sheen A; Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia.
  • Chou A; Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia.
  • Gill AJ; Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia.
  • Jansson PJ; Kolling Institute of Medical Research, University of Sydney, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
  • Sahni S; Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia. Electronic address: sumit.sahni@sydney.edu.au.
Eur J Pharmacol ; 973: 176568, 2024 Jun 15.
Article em En | MEDLINE | ID: mdl-38604544
ABSTRACT

BACKGROUND:

Triple negative breast cancer (TNBC) has the worst prognosis among breast cancer subtypes. It is characterized by lack of estrogen, progesterone and human epidermal growth factor 2 receptors, and thus, have limited therapeutic options. Autophagy has been found to be correlated with poor prognosis and aggressive behaviour in TNBC. This study aimed to target autophagy in TNBC via a novel approach to inhibit TNBC progression.

METHODS:

Immunoblotting and confocal microscopy were carried out to examine the effect of tumor microenvironmental stressors on autophagy. Cellular proliferation and migration assays were used to test the effect of different autophagy inhibitors and standard chemotherapy alone or in combination. In vivo xenograft mouse model was utilized to assess the effect of autophagy inhibitors alone or in combination with Paclitaxel. High resolution mass spectrometry based proteomic analysis was performed to explore the mechanisms behind chemoresistance in TNBC. Lastly, immunohistochemistry was done to assess the correlation between autophagy related proteins and clinical characteristics in TNBC tissue specimens.

RESULTS:

Metabolic stressors were found to induce autophagy in TNBC cell lines. Autophagy initiation inhibitors, SAR405 and MRT68921, showed marked synergy in their anti-proliferative activity in both chemosensitive and chemoresistant TNBC cell models. Paradoxically, positive expression of autophagosome marker LC3 was shown to be associated with better overall survival of TNBC patients.

CONCLUSION:

In this study, a novel combination between different autophagy inhibitors was identified which inhibited tumor cell proliferation in both chemosensitive and chemoresistant TNBC cells and could result in development of a novel treatment modality against TNBC.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Autofagia / Proliferação de Células / Neoplasias de Mama Triplo Negativas Limite: Animals / Female / Humans Idioma: En Revista: Eur J Pharmacol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Egito
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Autofagia / Proliferação de Células / Neoplasias de Mama Triplo Negativas Limite: Animals / Female / Humans Idioma: En Revista: Eur J Pharmacol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Egito