Combination of metformin and fec (5-fluorouracil, epirubicin, cyclophophasmide) chemotherapy as a potential therapy for targeting cancer stem cells in breast cancer / Soo Sian Siu

Soo , Sian Siu (2015) Combination of metformin and fec (5-fluorouracil, epirubicin, cyclophophasmide) chemotherapy as a potential therapy for targeting cancer stem cells in breast cancer / Soo Sian Siu. Masters thesis, University of Malaya.

[img] PDF (Content restricted: Please contact admin for further information)
Restricted to Repository staff only until 31 December 2017.

Download (7Mb)


    Cancer stem cells (CSCs) are a subpopulation of tumor cells with tumorigenic and stem-like properties and may drive tumor growth and maintenance. CSCs-targeting therapies should be incorporated into standard therapies to potentially prevent cancer progression, recurrence and metastasis. An anti-diabetic, AMPK-activating drug, metformin has been shown to kill CSCs and reduce cancer incidence and cancer related death. This study aimed to evaluate the combination treatment of metformin and other AMPK/mTOR-acting drugs with chemotherapy on breast CSCs and non-CSCs in the pre-clinical and clinical settings. We investigated the combination effect of metformin, AICAR, A-769662, or rapamycin with doxorubicin, cisplatin, paclitaxel or FEC (5-fluorouracil, epirubicin, cyclophophasmide) on breast CSCs and non-CSCs in vitro. The study was extended clinically in a pilot study of ten non-diabetic breast cancer patients treated with metformin and FEC chemotherapy as the neoadjuvant or 1st line chemotherapy for Stage II/III or IV patients, respectively. The proportions of ESA+/CD44+/CD24- (CSCs) in primary tumor samples and tumor responses before and after treatment were evaluated. In contrast to other AMPK/mTOR-targeting drugs and chemotherapeutic agents, metformin exhibited higher sensitivity in CSCs compared to non-CSCs enriched cell lines. Metformin, but not other AMPK agents, synergized breast CSCs and non-CSCs to FEC chemotherapy. Metformin targeted CSCs in an AMPK independent manner as inhibition of AMPK abolished metformin’s cytotoxic effect in non-CSCs but not CSCs. Metformin coupled with FEC chemotherapy iv significantly reduced the percentage of CSCs in primary tumor samples (P=0.008). Five out of eleven tumors (45.45%) evaluated showed either complete or partial response to the combination treatment where one tumor achieved pathological complete response (9.09%). In conclusion, metformin synergized FEC sensitivity in both CSCs and non-CSCs in breast cancer cell lines. Combination treatment of metformin and FEC reduced CSCs in primary tumors of non-diabetic breast cancer patients. These results indicate that neoadjuvant metformin/FEC may be a potential treatment option for breast cancer patients and warrants further clinical investigations.

    Item Type: Thesis (Masters)
    Additional Information: Dissertation (M.A.) Faculty of Medicine, University of Malaya, 2015.
    Uncontrolled Keywords: Combination of metformin and fec; Cancer stem cells; Breast cancer, Chemotherapy; Combination treatment
    Subjects: R Medicine > R Medicine (General)
    R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
    Divisions: Faculty of Medicine
    Depositing User: Mr. Nazirul Mubin Hamzah
    Date Deposited: 13 Apr 2017 12:43
    Last Modified: 13 Apr 2017 12:43

    Actions (For repository staff only : Login required)

    View Item