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Autophagy Inhibition Delays Early but Not Late-Stage Metastatic Disease
- Source :
- Journal of Pharmacology and Experimental Therapeutics. 358:282-293
- Publication Year :
- 2016
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2016.
-
Abstract
- The autophagy pathway has been recognized as a mechanism of survival and therapy resistance in cancer, yet the extent of autophagy’s function in metastatic progression is still unclear. Therefore, we used murine models of metastatic cancer to investigate the effect of autophagy modulation on metastasis development. Pharmacologic and genetic autophagy inhibition were able to impede cell proliferation in culture, but did not impact the development of experimentally induced 4T1 and B16-F10 metastases. Similarly, autophagy inhibition by adjuvant chloroquine (CQ) treatment did not delay metastasis in an orthotopic 4T1, tumor-resection model. However, neoadjuvant CQ treatment or genetic autophagy inhibition resulted in delayed metastasis development, whereas stimulation of autophagy by trehalose hastened development. Cisplatin was also administered either as a single agent or in combination with CQ. The combination of cisplatin and CQ was antagonistic. The effects of autophagy modulation on metastasis did not appear to be due to alterations in the intrinsic metastatic capability of the cells, as modulating autophagy had no impact on migration, invasion, or anchorage-independent growth in vitro. To explore the possibility of autophagy’s influence on the metastatic microenvironment, bone marrow–derived cells (BMDCs), which mediate the establishment of the premetastatic niche, were measured in the lung and in circulation. Trehalose-treated mice had significantly more BMDCs than either vehicle- or CQ-treated mice. Autophagy inhibition may be most useful as a treatment to impede early metastatic development. However, modulating autophagy may also alter the efficacy of platinum-based therapies, requiring caution when considering combination therapies.
- Subjects :
- Cellular and Molecular
0301 basic medicine
Time Factors
medicine.medical_treatment
Antineoplastic Agents
Apoptosis
Biology
Metastasis
Mice
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
Autophagy
medicine
Animals
Neoplasm Metastasis
Neoadjuvant therapy
Cell Proliferation
Neoplasm Staging
Pharmacology
Cisplatin
Cell growth
Trehalose
Cancer
Chloroquine
Drug Synergism
medicine.disease
Neoadjuvant Therapy
030104 developmental biology
Cell culture
030220 oncology & carcinogenesis
Immunology
Cancer research
Molecular Medicine
Female
medicine.drug
Subjects
Details
- ISSN :
- 15210103
- Volume :
- 358
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacology and Experimental Therapeutics
- Accession number :
- edsair.doi.dedup.....0c4b764ecc925eeb3ceb5c18c9e3f49a