Synergistic cytotoxicity of artemisinin and sodium butyrate on human cancer cells.

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Anticancer Res. 2005 Nov-Dec;25(6B):4325-31.

Synergistic cytotoxicity of artemisinin and sodium butyrate on human cancer cells.

Singh NP, Lai HC.
Department of Bioengineering, Box 357962, University of Washington, Seattle, WA 98195-7962, USA.

BACKGROUND:
Butyric acid is a short chain fatty acid produced by large bowel
bacterial flora. It serves as an antiinflammatory agent and nutrient
for normal colon cells. Butyric acid has also been shown to induce
apoptosis in colon and many other cancer cells. Artemisinin is a
compound extracted from the wormwood Artemisia annua L. It has been
shown to selectively kill cancer cells in vitro and to be effective in
treating animal and human cancer. We and others have found that the
artemisinin analog, dihydroartemisinin (DHA), kills cancer cells by
apoptosis. In the present study, the efficacy of a combined treatment
of DHA and butyric acid at low doses in killing cancer cells was
investigated.
MATERIALS AND METHODS: Molt-4 cells (a human
lymphoblastoid leukemia cell line) and freshly isolated human
lymphocytes, cultured in complete RPMI-1640 medium, were first
incubated with 12 microM of human holotransferrin at 37 degrees C in a
humid atmosphere of 5% CO2 for one hour to enhance the iron
concentration in the cells. Cells from each cell type were then divided
into 20 flasks. These flasks were grouped into four sets of five
cultures each. Zero, 5, 10 or 20 microM of DHA was added, respectively,
to these sets and the cells were incubated at 37 degrees C for one
hour. Zero, 1, 5, 10, or 20 mM of sodium butyrate was then added to the
five cultures of each set, respectively. Thus, the treatments involved
a combination of 4 doses of DHA and 5 doses of sodium butyrate. The
cells were counted immediately before the addition of DHA, and at 24
and 48 hours after the addition of sodium butyrate.
RESULTS: DHA alone
at the 24-hour time-point and 20 microM concentration significantly
reduced the number of Molt-4 cells in the culture by approximately 40%
(p < 0.001, compared to non-treated control), whereas it did not
significantly affect the number of normal human lymphocytes. Similarly,
1 mM sodium butyrate alone at 24 hours reduced the number of Molt-4
cells by approximately 32% (p < 0.001, compared to non-treated
control), without significantly affecting normal human lymphocytes. The
combination of 20 microM DHA and 1 mM sodium butyrate killed all Molt-4
cells at the 24-hour time-point and did not significantly affect
lymphocytes.
CONCLUSION: DHA in combination with butyric acid acts
synergistically at low doses. The combination may provide a less toxic,
inexpensive and effective cancer chemotherapy.