The antimalaria drug artemisinin displays strong cytotoxic effect on leukaemia lymphocytes in combination with vitamin C and pro-vitamin K3

Abstract

This study investigated the anticancer effect of the anti-parasitic drug artemisinin in combination with two redox modulators: vitamin C and pro-vitamin K3 (C/K3) The experiments were conducted on leukaemia cells Jurkat. Cells were treated with either artemisinin or C/K3 alone and with all three compounds. Cell proliferation and viability were analysed using trypan blue stating and automated cell counting. The results showed that artemisinin (>10 mM) suppressed cell proliferation activity, but did not induce cell death up to 500 mM. The drug demonstrated a clear cytostatic effect at concentrations 250- 500 mM – Jurkat cells did not proliferate, but were alive. The combination C/K3 (200:2, 300:3 mM/mM) applied alone did not affect cell proliferation and viability. Vitamins C/K3 in concentration ratio 500:5 (μM/mM) decreased cell proliferation activity by ~10%. The triple combination artemisinin/C/K3 manifested synergistic anti-proliferative effects at all concentration ratios analysed. This synergistic effect increased with increasing C/K3 concentration. Based on literature data, it was assumed that the anti-proliferative effect of the triple combination was mediated by changes in the redox-homeostasis of cancer cells. The C/K3 redox system likely acted on cancer mitochondria and increased superoxide production and activation of pro-apoptotic signals, specific for cancer cells. On the other hand, artemisinin could generate hydroxyl radicals as a result of activation of Fenton reactions, depleting intracellular reducing equivalents. Both redox mechanisms lead to activation of signal pathways for induction of cancer cell death.

Vitamin K: A novel cancer chemosensitizer

“…106 Artemisinin, an antimalaria drug in combination with vitamin K3/AA treatment manifested an antiproliferative effect synergistically but not cell death at all concentration ratios in leukemia. 91 In the case of urothelial carcinoma, vitamin K3/AA treatment has significantly augmented the antineoplastic activity of gemcitabine both in vivo and in vitro by inducing apoptosis and suppressing cell proliferation. 72 It has been reported that vitamin K3/AA treatment in the bladder, prostate, and ovarian cancer arrested cell cycle at Go/Gl, S, G2/M-phases, and induced cell death by necrosis, apoptosis, and autoschizis.…”

“…A pile of literature suggested that parallel to promising anticancer activity of vitamin K3, it has also a strong potential to act as a chemosensitizer for multiple drug‐resistant neoplasms such as colon 26 62 and HTC116 63 cell lines of colon cancer; AN3CA 64,65 cell line of uterine cancer; DU145, 66–68 PC3, 69–71 and LNCaP 71 cell lines of prostate cancer; UC and UMUC‐14 72 cell lines of urothelial cancer; A431 73 cells line of epidermoid carcinoma; 253JB‐V,T24 72,74–77 and RT4 77,78 cell lines of bladder cancer; KB‐V1 79 cell line of cervix carcinoma; MDA‐MB 231 63 and MCF‐7 62,64,71,79–84 cell lines of breast cancer; A172 71 and U87MG 63 cell lines of glioblastoma; CG1 85 cell line of nasopharyngeal carcinoma; MOLT‐4, 86 K562, 87,88 HL‐60, 89 Jurkat, 62,63,90–92 , and CCRF‐CEM, K562 90,63 cell lines of leukemia; TLT 93 and HepG2 82 cell lines of HCC; HeLa 94 cell line of human cervical adenocarcinoma; MRC‐5 82 A549 94,95 and HCT116 96 cell lines of human colorectal carcinoma; RCC and ACHN 82,97 cell lines of renal carcinoma; KB, 64 HSC‐2, HSC‐3, and HGF 89 cell lines of human oral squamous cell carcinoma; MDAH 2774 98 and NCI/ADR‐RES 83 cell lines of ovarian carcinoma; and PANC1 71 cell line of human pancreatic cancer as given in Table 3.…”

“…Its mechanism lies under the increased expression of urokinase plasminogen activator and reduction of MMP‐2, ‐3, and ‐9 by increased expression of tissue inhibitor of metalloproteinase (TIMP‐1, TIMP‐2, plasminogen activator inhibitor‐1, and nonmetastatic protein 23 homolog 1) 106 . Artemisinin, an antimalaria drug in combination with vitamin K3/AA treatment manifested an antiproliferative effect synergistically but not cell death at all concentration ratios in leukemia 91 . In the case of urothelial carcinoma, vitamin K3/AA treatment has significantly augmented the antineoplastic activity of gemcitabine both in vivo and in vitro by inducing apoptosis and suppressing cell proliferation 72 .…”