Sian Siu Soo

Date of Award

1-1-2015

Thesis Type

masters

Document Type

Thesis (Restricted Access)

Divisions

medic

Department

Faculty of Medicine

Institution

University of Malaya

Abstract

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.

Note

Dissertation (M.A.) Faculty of Medicine, University of Malaya, 2015.

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