SRC tyrosine kinase and multidrug resistance protein-1 inhibitions act independently but cooperatively to restore paclitaxel sensitivity to paclitaxel-resistant ovarian cancer cells
Open accessAbstract
Src tyrosine kinase has been found to be overexpressed in both mouse and human ovarian cancer cells as well as in human primary ovarian cancers. Furthermore, Src inhibition sensitizes ovarian cancer cells to chemotherapeutic agents such as paclitaxel and cisplatin. Interestingly, Src inhibition has also been shown to resensitize paclitaxel-resistant cells to the cytotoxic effects of paclitaxel. The current study was undertaken in an effort to determine the mechanism by which Src resensitizes drug-resistant ovarian cancer cells. The paclitaxel-resistant human (CaOV3TaxR) and mouse (ID8TaxR) ovarian cancer cell lines express large amounts of the multidrug resistance-1 (MDR-1) protein compared with the paclitaxel-sensitive parent cell lines. Src inhibition had no effect on MDR-1 protein expression. Furthermore, Src inhibition did not affect MDR-1 function as determined by rhodamine 123 and paclitaxel uptake or retention. Coinhibition of both Src and MDR-1 synergistically enhanced paclitaxel-induced cytotoxicity in paclitaxel-resistant ovarian cancer cell lines. Inhibition of Src enhanced microtubule stabilization in paclitaxel-resistant ovarian cancer cells treated with paclitaxel without affecting expression of β-tubulin isotypes and resulted in multipolar spindle formation and apoptosis. These results show that Src inhibition restores paclitaxel sensitivity to paclitaxel-resistant ovarian cancer cells by an MDR-independent mechanism, possibly by decreasing the critical intracellular concentration at which paclitaxel induces tubulin stabilization and bundling. Src tyrosine kinase may provide a viable target for therapeutic intervention in drug-resistant ovarian cancer.
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Preclinical evidence in sarcoma and ovarian cancer cell lines suggests that activation of Src reduces sensitivity to various chemotherapeutic drugs, including platinum agents, and that this resistance can be reversed by pharmacological inhibition.
“In addition, evidence from preclinical studies in sarcoma and ovarian cancer cell lines suggests that activation of Src reduces sensitivity to various chemotherapeutic drugs, including platinum agents, and that this resistance can be reversed by pharmacological inhibition [19, 20][21–23][24].”
From Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src (2016) · cites this paper as [23]
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References 26 · Cited by 78
- Authors
- George, J. A., Chen, T., & Taylor, C. C.
- Affiliations
- Georgetown University (US)
- Venue
- Cancer Research
- Published
- 2005-11-15
- Volume
- 65
- Issue
- 22
- Pages
- 10381-10388
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2034368878
- Cited by
- 78
- References
- 26
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 5 · 2013: 6 · 2012: 4
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
- Keywords
- Src kinase, multidrug resistance protein 1, paclitaxel resistance, ovarian cancer, drug resistance reversal, microtubule stabilization, apoptosis, chemoresistance
- MeSH terms
- Animals, Antineoplastic Agents, Phytogenic, Drug Synergism, Female, Humans, Microtubules, Ovarian Neoplasms, Tubulin, Up-Regulation, Paclitaxel, Drug Resistance, Neoplasm, src-Family Kinases, Protein Isoforms, ATP Binding Cassette Transporter, Subfamily B, Member 1, Cell Line, Tumor, Mice
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