Selective Cytostatic and Neurotoxic Effects of Avermectins and Activation of the GABAα Receptors

Kokoz, Yu. M.; Tsyganova, V. G.; Korystova, A. F.; Grichenko, A S; Zenchenko, K. I.; Drinyaev, V. A.; Mosin, V A; Kruglyak, E. B.; Sterlina, T. S.; Victorov, Alexander V.

doi:10.1023/a:1020262811459

Cited by 12 publications

(6 citation statements)

References 16 publications

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“…We have previously shown the cytotoxic effect of avermectins on hemocytes, leading to their death (Tomilova et al, 2016). Additionally, the cytostatic and cytotoxic effects of the avermectins complex on various cells of warm-blooded animals are well known (Sivkov, Yakovlev & Chashov, 1998; Kokoz et al, 1999; Korystov et al, 1999; Maioli et al, 2013). Increase in PO activity under the influence of avermectins could also be symptom linked with proliferation of bacteria (Fig.…”

Section: Discussionmentioning

confidence: 99%

Combined effect of the entomopathogenic fungusMetarhizium robertsiiand avermectins on the survival and immune response ofAedes aegyptilarvae

Noskov

Polenogova

Yaroslavtseva

et al. 2019

PeerJ

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Combination of insect pathogenic fungi and microbial metabolites is a prospective method for mosquito control. The effect of the entomopathogenic fungus Metarhizium robertsii J.F. Bischoff, S.A. Rehner & Humber and avermectins on the survival and physiological parameters of Aedes aegypti (Linnaeus, 1762) larvae (dopamine concentration, glutathione S-transferase (GST), nonspecific esterases (EST), acid proteases, lysozyme-like, phenoloxidase (PO) activities) was studied. It is shown that the combination of these agents leads to a synergistic effect on mosquito mortality. Colonization of Ae. aegypti larvae by hyphal bodies following water inoculation with conidia is shown for the first time. The larvae affected by fungi are characterized by a decrease in PO and dopamine levels. In the initial stages of toxicosis and/or fungal infection (12 h posttreatment), increases in the activity of insect detoxifying enzymes (GST and EST) and acid proteases are observed after monotreatments, and these increases are suppressed after combined treatment with the fungus and avermectins. Lysozyme-like activity is also most strongly suppressed under combined treatment with the fungus and avermectins in the early stages posttreatment (12 h). Forty-eight hours posttreatment, we observe increases in GST, EST, acid proteases, and lysozyme-like activities under the influence of the fungus and/or avermectins. The larvae affected by avermectins accumulate lower levels of conidia than avermectin-free larvae. On the other hand, a burst of bacterial CFUs is observed under treatment with both the fungus and avermectins. We suggest that disturbance of the responses of the immune and detoxifying systems under the combined treatment and the development of opportunistic bacteria may be among the causes of the synergistic effect.

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Section: Discussionmentioning

confidence: 99%

Combined effect of the entomopathogenic fungusMetarhizium robertsiiand avermectins on the survival and immune response ofAedes aegyptilarvae

Noskov

Polenogova

Yaroslavtseva

et al. 2019

PeerJ

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“…Oral ivermectin is already extensively used to treat parasite infections in humans including river blindness (63) with few side effects observed at clinical doses (64, 65). Selamectin and ivermectin do not readily cross the blood–brain barrier (66) and thus far only dogs with mutated ABCB1 (MDR1) and knockout mice for this gene have exhibited neurotoxicity (67) with these drugs. In summary, our results strongly suggests that selective inhibition of SIN3 function using selamectin or ivermectin should be investigated clinically in combinatorial adjuvant and neoadjuvant therapy, both with existing agents such as tamoxifen as well as molecularly-targeted drugs.…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of SIN3 Corepressor with Avermectins as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer

Kwon

Petrie

Leibovitch

et al. 2015

Molecular Cancer Therapeutics

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Triple negative breast cancers (TNBC) lacking estrogen, progesterone and HER2 receptors account for 10–20% of breast cancer and are indicative of poor prognosis. The development of effective treatment strategies therefore represents a pressing unmet clinical need. We previously identified a molecularly-targeted approach to target aberrant epigenetics of TNBC using a peptide corresponding to the SIN3 interaction domain (SID) of MAD. SID peptide selectively blocked binding of SID-containing proteins to the paired α-helix (PAH2) domain of SIN3, resulting in epigenetic and transcriptional modulation of genes associated with epithelial-mesenchymal transition (EMT). To find small molecule inhibitor (SMI) mimetics of SID peptide we performed an in silico screen for PAH2 domain-binding compounds. This led to the identification of the avermectin macrocyclic lactone derivatives selamectin and ivermectin (Mectizan) as candidate compounds. Both selamectin and ivermectin phenocopied the effects of SID peptide to block SIN3-PAH2 interaction with MAD, induce expression of CDH1 and ESR1 and restore tamoxifen sensitivity in MDA-MB-231 human and MMTV-Myc mouse TNBC cells in vitro. Treatment with selamectin or ivermectin led to transcriptional modulation of genes associated with EMT and maintenance of a cancer stem cell phenotype in TNBC cells. This resulted in impairment of clonogenic self-renewal in vitro and inhibition of tumor growth and metastasis in vivo. Underlining the potential of avermectins in TNBC, pathway analysis revealed that selamectin also modulated the expression of therapeutically-targetable genes. Consistent with this, an unbiased drug screen in TNBC cells identified selamectin-induced sensitization to a number of drugs, including those targeting modulated genes.

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“…Ivermectin has a good safety profile since only in‐vivo ‐dnTCF‐sensitive cancer xenografts are responsive to Ivermectin treatment, and we have not detected side effects in Ivermectin‐treated mice at the doses used. Whereas it remains likely that higher doses may begin to show non‐specific toxicity, previous work has shown that side effects from systemic treatments with clinically relevant doses in humans are rare (Yang, ), that birth defects were not observed after exposure of pregnant mothers (Pacqué et al , ) and that this drug does not cross the blood–brain barrier (Kokoz et al , ). Similarly, only dogs with mutant ABCB1 (MDR1) alleles leading to a broken blood–brain barrier show Ivermectin neurotoxicity (Mealey et al , ; Orzechowski et al , ).…”

Section: Discussionmentioning

confidence: 99%

The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT‐TCF pathway responses in human cancer

et al. 2014

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Constitutive activation of canonical WNT-TCF signaling is implicated in multiple diseases, including intestine and lung cancers, but there are no WNT-TCF antagonists in clinical use. We have performed a repositioning screen for WNT-TCF response blockers aiming to recapitulate the genetic blockade afforded by dominant-negative TCF. We report that Ivermectin inhibits the expression of WNT-TCF targets, mimicking dnTCF, and that its low concentration effects are rescued by direct activation by TCFVP16. Ivermectin inhibits the proliferation and increases apoptosis of various human cancer types. It represses the levels of C-terminal β-CATENIN phosphoforms and of CYCLIN D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases.In vivo, Ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without obvious side effects. Analysis of single semi-synthetic derivatives highlights Selamectin, urging its clinical testing and the exploration of the macrocyclic lactone chemical space. Given that Ivermectin is a safe anti-parasitic agent used by > 200 million people against river blindness, our results suggest its additional use as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers.

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Selective Cytostatic and Neurotoxic Effects of Avermectins and Activation of the GABAα Receptors

Cited by 12 publications

References 16 publications

Combined effect of the entomopathogenic fungusMetarhizium robertsiiand avermectins on the survival and immune response ofAedes aegyptilarvae

Combined effect of the entomopathogenic fungusMetarhizium robertsiiand avermectins on the survival and immune response ofAedes aegyptilarvae

Selective Inhibition of SIN3 Corepressor with Avermectins as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer

The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT‐TCF pathway responses in human cancer

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