Salinomycin, as an autophagy modulator-- a new avenue to anticancer: a review

Abstract

Since Salinomycin (Sal) emerged its ability to target breast cancer stem cells in 2009, numerous experiments have been carried out to test Sal’s anticancer effects. What deserve to be mentioned is that Sal can efficiently induce proliferation inhibition, cell death and metastasis suppression against human cancers from different origins both in vivo and in vitro without causing serious side effects as the conventional chemotherapeutical drugs on the body. There may be novel cell death pathways involving the anticancer effects of Sal except the conventional pathways, such as autophagic pathway. This review is focused on how autophagy involves the effects of Sal, trying to describe clearly and systematically why autophagy plays a vital role in predominant anticancer effects of Sal, including its distinctive characteristic. Based on recent advances, we present evidence that a dual role of Sal involving in autophagy may account for its unique anticancer effects - the preference for cancer cells. Further researches are required to confirm the authenticity of this suppose in order to develop an ideal anticancer drug.

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…271 Salinomycin is a drug that must be used at strictly limited concentrations, due to its potential neurotoxicity. 275 Hence, theoretically both salinomycin and CQ can be combined with DNA repair inhibitors. To this end, under the acidic conditions that inhibit CQ activity, salinomycin reaches the acidic core of multicellular tumor spheroids and impairs the autophagic flux, thereby killing malignant cells.…”

“…277 In addition to impairing DNA maintenance, DNA-PK inhibitors could affect immune responses at several levels, and therefore the kinetics and dynamics of adding them to a combination treatment scheme need to be studied. 275,279 Hence, the mechanisms through which salinomycin activates autophagy apparently make cancer cells prone to cell death, depending on the downstream signals it elicits. Salinomycin can induce autophagy via AMPK, and in parallel inhibit autophagy at later stages: thereby salinomycin use exploits the imbalanced induction of autophagic pathway components that takes place in some cancer cell types.…”

“…In line with the potential of CQ for synergy with inhibitors of DNA repair, the antineoplastic effect of salinomycin is neutralized by the induction of DNA repair via DNA-protein kinase (DNA-PK) enzymes. 275 Hence, theoretically both salinomycin and CQ can be combined with DNA repair inhibitors.…”

“…Salinomycin can induce autophagy via AMPK, and in parallel inhibit autophagy at later stages: thereby salinomycin use exploits the imbalanced induction of autophagic pathway components that takes place in some cancer cell types. 275,279 Hence, the mechanisms through which salinomycin activates autophagy apparently make cancer cells prone to cell death, depending on the downstream signals it elicits. This is probably the main reason that salinomycin can sensitize some cells to CQ.…”

Autophagy and Cell Death: Antitumor Drugs Targeting Autophagy

“…Salinomycin does not only induce apoptosis in CSCs but also inhibits DNA repair of CSCs. Interestingly, the proliferation of CSCs is inhibited by the increase or decrease of autophagic activity after the action of salinomycin [33]. On the one hand, after the action of salinomycin, the increase of reactive oxygen species (ROS) activates c-Jun N-terminal kinase (JNK) and AMPK signaling pathways to induce an increase of autophagy activity; on the other hand, salinomycin also affects the process of autophagosome and lysosome fusion and reduces the level of autophagic flux.…”