Antitumor effect of the combination of exogenous sphingosine-1-phosphate(S1P), S1P receptor 1(S1PR1) antibody and carboplatin against human breast cancer cells
Date
2018-10-02
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0000-0001-9311-7758
Type
Thesis
Degree Level
Masters
Abstract
Breast cancer is the third most common cancer in Canada. Even though the morbidity and mortality rates have reduced in recent years because of early diagnosis and improved treatments, new treatment methods or therapeutic agents are still needed to deal with cases such as low response rates with triple negative breast cancer, rapid drug resistance, and side effects caused by breast cancer treatment.
Sphingolipids have been reported to play an important role in breast cancer tumorigenesis. Sphingosine-1-phosphate (S1P), a pleiotropic lysophospholipid mediator, can regulate S1P receptor (S1PR)-dependent or S1PR-independent cell proliferation, apoptosis, autophagy, migration, survival, angiogenesis, and differentiation. Previous studies from our laboratory have shown that S1P can selectively cause cell death in breast cancer cell lines MDA-MB-231 and MCF-7.
Our previous studies have shown that S1P exhibits synergistic effects with docetaxel, doxorubicin, and cyclophosphamide towards human breast cancer MDA-MB-231 and MDA-MB-361 cells. Since carboplatin is a commonly prescribed DNA alkylating agent and approved for advanced breast cancer, I investigated whether S1P or S1PR1 antibody can enhance the cytotoxic effect of carboplatin towards human breast cancer MCF-7, SK-BR-3, and MDA-MB-231 cells.
In this study, S1PR1 antibody was shown to exhibit cytostatic effect against the MCF-7, SK-BR-3 and MDA-MB-231 cell lines. Co-administration of 4,000 ng/mL of the S1PR1 antibody not only potentiated the cytotoxicity of carboplatin towards the MDA-MB-231 cells but also increased the anti-proliferative effect of S1P towards SK-BR-3 cells. Furthermore, we showed that co-administration of S1P did not sensitize the MCF-7, SK-BR-3 and MDA-MB-231 cells towards carboplatin. In the future, co-administration of 4,000 ng/mL S1PR1 antibody with carboplatin, as well other chemotherapy drugs such as docetaxel, paclitaxel and doxorubicin, will be evaluated against more breast cancer cell lines, and the mechanism on how S1PR1 antibody enhances cytotoxicity of carboplatin on breast cancer cells will be studied.
Description
Keywords
Breast cancer, sphingosine-1-phosphate, S1P receptor 1, carboplatin
Citation
Degree
Master of Science (M.Sc.)
Department
Pharmacy and Nutrition
Program
Pharmacy