Abstract
Artemisinin (ART) and dihydroartemisinin (DHA) are anti-malaria drugs but also exhibit huge anticancer potential based on ferroptosis driven by iron-dependent lipid peroxidation. This study was conducted on primary (SW480), metastatic (SW620) colon cancer, and noncancerous HaCaT cells at pharmacologically relevant drug concentrations (1–8 µM) and in the presence of holotransferrin (TRFi 50 µM) and linoleic acid (LA 20, 40 µM) at physiological levels. ART and DHA showed the growth inhibitory potency which was significantly increased in the presence of LA or/and TRFi. The IC50 for ART or DHA, LA40 and TRFi combination in both cancer cell lines ranged 0.14–0.69 µM whereas no cytotoxic effect was observed for HaCaT cells (SI = 202–480). Almost all experimental settings revealed late apoptosis in both cancer cell lines, but not in normal cells. The percentage of late apoptotic cells increased with LA concentrations and was intensified after TRFi addition. The strongest pro-apoptic effect was exhibited by ART or DHA, LA40, and TRFi combination. More interestingly, we found a stimulatory effect of TRFi on IL-6 synthesis. The present study using LA and TRFi which are inherent blood components revealed high antitumor artemisinin activity in concentrations achievable after drug administration to cancer patients without toxic effects on normal cells.
Highlights
A cytotoxic potency against tumor cells for tested compounds was expressed as a selectivity factor
The IC50 values calculated for HaCaT cells were several times higher compared to the studied colon cancer (SW480, SW620) cells, while the mixture of ART or DHA and LA with TRFi showed about an eight-fold higher cytotoxicity activity against cancer cells in comparison to the same mixture without TRFi (Table 1)
We found a decrease in IC50 for both ART and DHA at the presence of TRFi compared to drugs alone (4.58 vs. 39 and 1.64 vs. 11.4 in SW480 and 16.3 vs. 42.8 and 10.3 vs. 11.9 in SW620 for ART and DHA, respectively), which was more pronounced in primary colon cancer cells
Summary
Colorectal cancer (CRC) is the third-most-common malignant tumor in Poland and the fourth-rated as the leading cause of deaths in worldwide. Early screening, diagnosis improvement, and CRC treatment increased the 5-year survival rate of patients, to some extent, the proliferation and metastasis of tumor still present challenges in the treatment of CRC [1]. Various treatment options are available (surgery, radiotherapy, and adjuvant chemotherapy), in many cases these therapies are marked by a high level of toxicity to healthy cells, and drug resistance quickly develops in some treatment regimens [2,3,4]. One major challenge to reducing the adverse effects of the cancer burden is to develop highly effective drugs with specificity on cancers but little or no side effects on normal cells
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