Abstract:Background:
Artemisinin is a sesquiterpene lactone compound with a special peroxide bridge that is tightly linked to the cytotoxicity involved in fighting malaria and cancer. Artemisinin and its derivatives (ARTs) are considered to be potential anticancer drugs that promote cancer cell apoptosis, induce cell cycle arrest and autophagy, inhibit cancer cell invasion and migration. Additionally, ARTs significantly increase intracellular reactive oxygen species (ROS) in cancer cells, which results in ferroptosis, … Show more
“…As diminished levels of NCOA4 dampen ferritinophagy ferritins, especially FTMT, increases with the ability to interfere with RSL-3-induced ferroptosis. Since ferroptosis is discussed as a strategy for tumor therapy and hypoxia appears as a cardinal sign of many tumors, we intended to explore the role of ferritins and NCOA4 in ferroptosis of HT1080 fibrosarcoma cells [ [42] , [43] , [44] ]. Fig.…”
Cellular iron, at the physiological level, is essential to maintain several metabolic pathways, while an excess of free iron may cause oxidative damage and/or provoke cell death. Consequently, iron homeostasis has to be tightly controlled. Under hypoxia these regulatory mechanisms for human macrophages are not well understood. Hypoxic primary human macrophages reduced intracellular free iron and increased ferritin expression, including mitochondrial ferritin (FTMT), to store iron. In parallel, nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy, decreased and was proven to directly regulate FTMT expression. Reduced NCOA4 expression resulted from a lower rate of hypoxic NCOA4 transcription combined with a micro RNA 6862-5p-dependent degradation of NCOA4 mRNA, the latter being regulated by c-jun N-terminal kinase (JNK). Pharmacological inhibition of JNK under hypoxia increased NCOA4 and prevented FTMT induction. FTMT and ferritin heavy chain (FTH) cooperated to protect macrophages from RSL-3-induced ferroptosis under hypoxia as this form of cell death is linked to iron metabolism. In contrast, in HT1080 fibrosarcome cells, which are sensitive to ferroptosis, NCOA4 and FTMT are not regulated. Our study helps to understand mechanisms of hypoxic FTMT regulation and to link ferritinophagy and macrophage sensitivity to ferroptosis.
“…As diminished levels of NCOA4 dampen ferritinophagy ferritins, especially FTMT, increases with the ability to interfere with RSL-3-induced ferroptosis. Since ferroptosis is discussed as a strategy for tumor therapy and hypoxia appears as a cardinal sign of many tumors, we intended to explore the role of ferritins and NCOA4 in ferroptosis of HT1080 fibrosarcoma cells [ [42] , [43] , [44] ]. Fig.…”
Cellular iron, at the physiological level, is essential to maintain several metabolic pathways, while an excess of free iron may cause oxidative damage and/or provoke cell death. Consequently, iron homeostasis has to be tightly controlled. Under hypoxia these regulatory mechanisms for human macrophages are not well understood. Hypoxic primary human macrophages reduced intracellular free iron and increased ferritin expression, including mitochondrial ferritin (FTMT), to store iron. In parallel, nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy, decreased and was proven to directly regulate FTMT expression. Reduced NCOA4 expression resulted from a lower rate of hypoxic NCOA4 transcription combined with a micro RNA 6862-5p-dependent degradation of NCOA4 mRNA, the latter being regulated by c-jun N-terminal kinase (JNK). Pharmacological inhibition of JNK under hypoxia increased NCOA4 and prevented FTMT induction. FTMT and ferritin heavy chain (FTH) cooperated to protect macrophages from RSL-3-induced ferroptosis under hypoxia as this form of cell death is linked to iron metabolism. In contrast, in HT1080 fibrosarcome cells, which are sensitive to ferroptosis, NCOA4 and FTMT are not regulated. Our study helps to understand mechanisms of hypoxic FTMT regulation and to link ferritinophagy and macrophage sensitivity to ferroptosis.
“…[122][123][124] Recent results indicated ARS and its derivatives also had anticancer activity attributed to inducing non-apoptotic programmed cell death. 54,125,126 For instance, artesunate (ART)based agents stimulated ROS generation and promoted the lysosome degradation of ferritin instead of autophagic degradation, resulting in system X c -/GPX4 axis-mediated ferroptosis in cancer cells. 127 Similarly, Chen et al found that DHA sensitized cancer cells to ferroptosis by autophagic independent degradation of ferritin, inducing free iron accumulation and subsequently iron homeostasis dysregulation due to binding to the ironresponsive element sequences of iron-regulatory proteins.…”
Section: Non-oncology Drugs In Drug Repurposingmentioning
Ever present hurdles for the discovery of new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the development of old drugs for new therapeutic purposes. This strategy with a cost-effective way offers a rare opportunity for the treatment of human neoplastic disease, facilitating rapid clinical translation. With an increased understanding of the hallmarks of cancer and the development of various data-driven approaches, drug repurposing further promotes the holistic productivity of drug discovery and reasonably focuses on target-defined antineoplastic compounds. The "treasure trove" of non-oncology drugs should not be ignored since they could target not only known but also hitherto unknown vulnerabilities of cancer. Indeed, different from targeted drugs, these old generic drugs, usually used in a multi-target strategy may bring benefit to patients. In this review, aiming to demonstrate the full potential of drug repurposing, we present various promising repurposed non-oncology drugs for clinical cancer management and classify these candidates into their proposed administration for either mono-or drug combination therapy. We also summarize approaches used for drug repurposing and discuss the main barriers to its uptake.
“…Excessive production of ROS causes death by damaging cellular components, including DNA, proteins, and lipids ( 94 ); a notable feature of ARTs is that they can spontaneously generate a large amount of ROS in a heme-dependent manner ( 95 – 97 ). Many studies have indicated that ARTs increase the expression of cleaved caspase-3 and PARP in a variety of cancer cells by producing excessive amounts of ROS, thus inducing apoptosis in cancer cells ( 98 – 100 ). Further, excessive amounts of ROS may trigger an ER stress response in cancer cells ( 99 ), but the specific mechanism is not clear.…”
Section: Progress On the Use Of Artemisinin And Its Derivatives For Treating Cancermentioning
confidence: 99%
“…In the first mechanism, the expression of the core enzyme GPX4 in the antioxidant system is reduced or inactivated, depending on the level of intracellular GSH ( 116 ). In the second mechanism, unstable iron ions accumulate in cancer cells ( 100 ). The accumulation of unstable iron ions may be the main mechanism by which ART-induced ferroptosis.…”
Section: Progress On the Use Of Artemisinin And Its Derivatives For Treating Cancermentioning
Drug repositioning is a strategy for identifying new antitumor drugs; this strategy allows existing and approved clinical drugs to be innovatively repurposed to treat tumors. Based on the similarities between parasitic diseases and cancer, recent studies aimed to investigate the efficacy of existing antiparasitic drugs in cancer. In this review, we selected two antihelminthic drugs (macrolides and benzimidazoles) and two antiprotozoal drugs (artemisinin and its derivatives, and quinolines) and summarized the research progresses made to date on the role of these drugs in cancer. Overall, these drugs regulate tumor growth via multiple targets, pathways, and modes of action. These antiparasitic drugs are good candidates for comprehensive, in-depth analyses of tumor occurrence and development. In-depth studies may improve the current tumor diagnoses and treatment regimens. However, for clinical application, current investigations are still insufficient, warranting more comprehensive analyses.
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