Mechanistic Investigation of the Specific Anticancer Property of Artemisinin and Its Combination with Aminolevulinic Acid for Enhanced Anticolorectal Cancer Activity

Abstract

The antimalarial artemisinin (ART) possesses anticancer activity, but its underlying mechanism remains largely unclear. Using a chemical proteomics approach with artemisinin-based activity probes, we identified over 300 specific ART targets. This reveals an anticancer mechanism whereby ART promiscuously targets multiple critical biological pathways and leads to cancer cell death. The specific cytotoxicity of ART against colorectal cancer (CRC) cells rather than normal colon epithelial cells is due to the elevated capacity of heme synthesis in the cancer cells. Guided by this mechanism, the specific cytotoxicity of ART toward CRC cells can be dramatically enhanced with the addition of aminolevulinic acid (ALA), a clinically used heme synthesis precursor, to increase heme levels. Importantly, this novel ART/ALA combination therapy proves to be more effective than an ART monotherapy in a mouse xenograft CRC model. Thus, ART can be repurposed and potentiated by exploitation of its mechanism of action and the metabolic features of the CRC cells.

Targeting autophagy enhances the anticancer effect of artemisinin and its derivatives

“…Our previous studies demonstrated that ART activates lysosomal function and induces autophagy in HCT116 and HeLa cells, which is attributed to the suppression of mTOR activity. It was also reported that ART induces autophagy in chondrocytes through the increase of Beclin1 expression and the decrease of PI3K, AKT, and mTOR phosphorylation, indicating the suppression of the PI3K‐AKT‐mTOR pathway.…”

“…In vivo, many human tumor xenograft models also show the anticancer effect of artemisinin in both subcutaneously and orthotopically transplanted tumors . Similar to the activation of artemisinin in malaria, the high levels of free heme synthesized in the mitochondria of cancer cells leads to the activation of artemisinin's anticancer properties . Using a synthesized mitochondria‐targeted probe called artemisinin‐triphenylphosphonium bromide (artemisinin‐TPP), we observed increased potency of the anticancer effect of artemisinin‐TPP compared with that of the parent compound .…”

“…In the presence of free ferrous iron, the endoperoxide bridge of artemisinin and its derivatives is cleaved, resulting in free radical generation that leads to cellular and protein damage, eventually causing parasite death . In addition to free ferrous iron, our previous study revealed that heme is, in fact, the principal activator of artemisinin. The digestion of heme by malaria‐inducing parasites results in the release of copious heme and artemisinin activation (Figure ) .…”

“…Using a synthesized mitochondria‐targeted probe called artemisinin‐triphenylphosphonium bromide (artemisinin‐TPP), we observed increased potency of the anticancer effect of artemisinin‐TPP compared with that of the parent compound . Furthermore, cotreatment of cancer cells with ART and aminolevulinic acid (ALA, an Food and Drug Administration‐approved heme synthesis precursor) greatly enhanced the anticancer properties of artemisinin both in vitro and in vivo . Given that both of these drugs are clinically approved and known to be well tolerated, this combination represents a strategy that could potentially be quickly and safely adapted to clinical trials.…”

Totalsynthese und Untersuchung der biologischen Aktivität von (−)‐Artemisinin – die Antimalaria‐Aktivität von Artemisinin ist nicht stereospezifisch

“…[11,12] ¾hnliche Untersuchungen wurden von Ismail et al durchgeführt. Wang et al haben vor kurzem eine Vielzahl von Artemisinin-bindenden Proteinen von Plasmodium falciparum entdeckt.…”