Artemisinin induces doxorubicin resistance in human colon cancer cells via calcium‐dependent activation of HIF‐1α and P‐glycoprotein overexpression

Abstract

Background and purpose:Artemisinin is an antimalarial drug exerting pleiotropic effects, such as the inhibition of the transcription factor nuclear factor-kappa B and of the sarcoplasmic/endoplasmic reticulum Ca ]i) and Pgp expression and decreased doxorubicin accumulation and cytotoxicity. The intracellular Ca ++ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, and the inhibitor of calmodulin-dependent kinase II (CaMKII) KN93 prevented these effects. CaMKII is known to promote the phosphorylation and the activation of HIF-1a, which may induce Pgp. In HT29 cells, artemisinin and parthenolide induced the phosphorylation of HIF-1a, which was inhibited by KN93. Conclusions and implications:Our results suggest that artemisinin and parthenolide may act as SERCA inhibitors and, like other SERCA inhibitors, induce resistance to doxorubicin in human colon cancer cells, via the CaMKII-dependent activation of HIF-1a and the induction of Pgp.

In vitro study of the anti-cancer effects of artemisone alone or in combination with other chemotherapeutic agents

“…Generally, combining artemisinins with other drugs have increased the anti-tumour effect; however, ART has been shown to hinder some treatments via up-regulation of calmodulin signalling [46]. The present study…”

Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer

“…In fast-growing tumors, HIF-1· plays crucial roles in the activation of numerous cellular processes, including cell immortalization, cell growth and survival, invasion/metastasis, angiogenesis, resistance to chemotherapy, and overexpression of drug efflux membrane pumps (28,29). A recent report has shown that artemisinin induces DOX resistance by decreasing DOX accumulation and cytotoxicity in human colon cancer cells through the activation of HIF-1· and P-gp overexpression (30). Lau and coworkers have shown in an orthotropic HCC model that combining blockade of HIF-1· activity and ischemic hypoxia significantly enhanced the efficacy of chemotherapy, leading to the suppression of tumor growth and prolongation of animal survival; this suggests that blockade of HIF-1· autocrine signaling may enhance the chemosensitivity of liver cancer cells under hypoxic conditions (31).…”

The Interaction Between Redox and Hypoxic Signalling Pathways in the Dynamic Oxygen Environment of Cancer Cells

“…One highly studied ABC transporter protein is P-glycoprotein (Pgp) (an MDR1 gene product) that has been linked to MDR in cancer cells [110]. High levels of Pgp are found in MDR cells and coincide with higher expression of HIF-1 [111][112][113]. Doublier and co-workers found MCF7 breast cancer cells grown under hypoxia to be resistant to doxorubicin.…”