A comparison of low-dose cyclophosphamide treatment with artemisinin treatment in reducing the number of regulatory T cells in murine breast cancer model.
BACKGROUND
Artemisinin (ART) is a sesquiterpene lactone. Possessing an endoperoxide bridge is unique among antimalarial drugs, and now much attention is focused on the anti-cancer properties of ART. In this study we aimed at the immunomodulatory effects of artemisinin in the treatment of breast cancer in comparison to the conventional anti-cancer drug, cyclophosphamide (CTX).


METHODS
We examined delayed-type hypersensitivity, antibody and IL-4 and IFN gamma production, tumour volume, tumour infiltrated regulatory T cells (Treg) and spleen lymphocyte proliferation assay. Briefly three groups of five 4-6 week old female Balb/c tumour-bearing mice (mouse mammary tumour) were treated with 2.8 mg/kg ART and 20mg/kg CTX intraperitoneally for 20 consecutive days. Tumour volume was measured using a digital vernier calliper (with accuracy of 0.01). Mice were sacrificed and percentage of tumour infiltrating Tregs were obtained using flow cytometry (BD, USA). Proliferation of splenocytes was obtained using BrdU proliferation assay (Roche).


RESULTS
Our results showed that ART can reduce the number of Tregs in tumour stroma (P-value <or=0.047) as compared to CTX (P-value>or=0.05) and control. Furthermore ART increased IFN gamma/IL-4 ratio produced in splenocyte culture (P-value <or=0.001). Proliferation assay did not show any significant difference (P-value >or=0.05).


CONCLUSIONS
Cancer is a multi-factorial disease which needs a multi-approach treatment. Early accumulation of Treg cells in the tumour tissue correlates with tumour progression and is an indication of bad prognosis. According to the obtained results, ART can reduce the number of Tregs. We suggest using artemisinin, with its dual action mechanism. It can effectively kill cancer cells along with reducing the suppressive microenvironment.
Langroudi
Ladan
L
Department of Immunology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran. lnlangroudi@modares.ac.ir
Hassan
Zuhir Muhammad
ZM
Ebtekar
Massoumeh
M
Mahdavi
Mehdi
M
Pakravan
Nafise
N
Noori
Shokoofe
S
D000818:Animals; D000912:Antibodies, Neoplasm / Q000032:analysis / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D037621:Artemisinins / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000276:immunology; D003520:Cyclophosphamide / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D007371:Interferon-gamma / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D037621:Artemisinins; D015847:Interleukin-4; D007371:Interferon-gamma; D003520:Cyclophosphamide; C031327:artemisinin