The in vitro and in vivo antitumor activities of ivermectin are achieved at concentrations that can be clinically achieved based on human pharmacokinetic studies done in the clinical studies. Moreover, repurposed ivermectin safety has been well established recently in clinical studies against COVID-19.

Consequently, we believe that ivermectin is an excellent potential candidate drug that can be repurposed for cancer and deserves rigorous evaluation against a variety of cancers in well-designed clinical trials.

Cancer targets of ivermectin

1. Decreasing the function of the mitochondrial complex I, Ivermectin, limits the electronic movement in the oxidative phosphorylation pathway that stimulates oxygen consumption rate to generate ATP for the cell. Low ATP levels are related to a failure in the P-glycoprotein pump to extrude chemotherapy drugs. Concomitantly there is a reduction in the phosphorylation levels of Akt, impacting the mitochondrial biogenesis process. Furthermore, alterations in the mitochondrial machinery are related to increased levels of reactive oxygen species that damage DNA.

2. Ivermectin limits the function of the RNA helicases NS3 and DDX23, both of which are related to ribosome biogenesis and post-transcriptional modifications, as well as with mRNA degradation. DDX23 acts as a promoter of miR-21, which is a well-recognized stimulator of tumor progression.

3. The WNT-TCF pathway, involved in cancer progression and metastases, is inhibited by Ivermectin. Indeed, this compound represses AXIN2, LGR5, and ASCL2, all of them WNT-TCF targets. At the same time, it promotes the repressor of the WNT signaling FILIP1L. Both effects inhibit the ability of WNT-TCF to downregulate the tumor suppressor APC and limit the translocation of ß–catenin to the nucleus for epithelial to mesenchymal transition in metastatic events.

4. Ivermectin acts as an ionophore by the up-regulation of chloride channels to generate apoptosis and osmotic cell death.

5. Ivermectin induces immunogenic cell death by stimulating an ATP- and HMGB1-enriched microenvironment, which promotes inflammation. This drug also increases ATP sensitivity and calcium signals in P2X membranal receptors, particularly P2X4 and P2X7, to induce ATP-dependent immune responses.

6. Ivermectin promotes the poly-ubiquitination of the kinase PAK1, which directs it to degradation in the proteasome. Defective PAK1, in turn, inhibits the Akt/mTOR pathway. At the same time, Ivermectin stimulates the expression of Beclin1 and Atg5, both related to induction of autophagy. Particularly, Beclin1 increases the expression of the positive autophagy regulators Atg14L and Vps34 and reduces the negative regulator of apoptosis Bcl-2. Together, this generates autophagy and apoptosis.

7,8. Ivermectin modifies the epigenetic signature and the self-renewal activity in the malignant cell due to its ability to mimic the SIN3-interaction that binds to the PAH2 motif of the ca.