Given the increasing role of inhibitors of autophagy, I would like to discuss the choice of an inhibitor of autophagy, as well as the possibility of enhancing their effect.
___________________________________
This study focuses on the comparison of some of these inhibitors:
2015 http://thejns.org/doi/10.3171/2014.12.FOCUS14748
"...the authors of this study set out to investigate whether chloroquine (CQ) analogs, in particular clinically established antimalaria drugs, would also be able to exert antitumor properties, with a specific focus on glioma cells.
...the authors treated different glioma cell lines with quinine (QN), quinacrine (QNX), mefloquine (MFQ), and hydroxychloroquine (HCQ) and investigated endoplasmic reticulum (ER) stress–induced cell death, autophagy, and cell death.
All agents blocked cellular autophagy and exerted cytotoxic effects on drug-sensitive and drug-resistant glioma cells with varying degrees of potency (QNX > MFQ > HCQ > CQ > QN)."
Thus, it follows from the study that cloroquine (CQ) shows a weak effect, even lower, that hydroxychloroquine (HCQ) (?!) Maybe this explains the choice of hydroxychloroquine instead of chloroquine in some tests?
And another quotes from the study:
"Cytotoxicity of QBAs for Glioma Cells:
To determine whether other quinoline-based antimalarial (QBA) compounds could mimic the cytotoxic effects of CQ in glioma cells, we used MFQ and QNX. Results showed that these drugs effectively killed U251 cells at much lower concentrations than CQ."
Blocking Autophagy and Inducing Apoptosis in Glioma Cells:
Based on information that CQ induces apoptosis by blocking autophagy, we analyzed whether the other QBA compounds can function in a similar manner.
Quinacrine, the most potent QBA, not only blocked autophagy, but at 20 μM it completely disrupted U251 cellular functioning, which was evidenced by a high level of PARP cleavage, as well as the absence of CHOP/GADD-153 and LC3B expression.
In Vivo Antitumor Activity:
The TUNEL assay for apoptosis demonstrated a significant increase in the number of TUNEL-positive cells in QNX- and QN-> MFQ-> CQ-treated tumors, as compared with untreated controls."
There are also many reports of another inhibitor of autophagy - 3-methyladenine (3-MA).
___________________________________
Since many people here take chloroquine, I would like to discuss the possibility of enhancing its effect. While I see there are the following options:
chloroquine + cimetidine
"Cimetidine pre-treatment caused a 53% decrease in the clearance rate of chloroquine, and a 49% increase in the elimination half-life. Cimetidine inhibited the conversion of chloroquine to monodesethylchloroquine in terms of reductions in the AUC, Cmax, and urinary excretion of monodesethylchloroquine. The serum Cmax of chloroquine was increased by approximately 30% in the cimetidine pre-treated group."
The downside is that since there are many medicines in the cocktail, numerous unpredictable interactions with cimetidine are possible.
increase in the dose of Chloroquine
Instead of using cimetidine, can it be easier to increase the dose of Chloroquine? The standard is 250 mg / day.
chloroquine + hypoxia-inducing agents
2017 https://www.ncbi.nlm.nih.gov/pubmed/28797031
"This work shows that inhibition of autophagy is a promising strategy against GBM and identifies ATG9 as a novel target in hypoxia-induced autophagy. Combination with hypoxia-inducing agents may provide benefit by allowing to decrease the effective dose of autophagy inhibitors."
What hypoxia-inducing agents are they talking about?
___________________________________
I also found several preliminary studies on the synergy of chloroquine and other drugs. It is interesting to study more ..
Dihydroartemisinin + Сhloroquine
2017 https://www.ncbi.nlm.nih.gov/pubmed/29033794
Dihydroartemisinin Exerts Anti-Tumor Activity by Inducing Mitochondrion and Endoplasmic Reticulum Apoptosis and Autophagic Cell Death in Human Glioblastoma Cells.
"Co-treatment with chloroquine (CQ) significantly induced the above effects. Furthermore, ER stress and mitochondrial dysfunction were involved in the dihydroartemisinin-induced autophagy."
Asparaginase + Сhloroquine
2017 https://www.ncbi.nlm.nih.gov/pubmed/29207624
"combination treatment with autophagy inhibitor CQ significantly enhanced anti-glioblastoma efficacy of asparaginase in U87MG cell xenograft model."
Sorafenib + Сhloroquine
2016 https://www.ncbi.nlm.nih.gov/pubmed/26971793
"we combined sorafenib treatment in GBM cells (U373 and LN229) and tumors with the autophagy inhibitor chloroquine. We found that blockage of autophagy further inhibited cell proliferation and migration and induced cell apoptosis in vitro and in vivo. These findings suggest the possibility of combination treatment with sorafenib and autophagy inhibitors for GBM."
___________________________________
2015 http://thejns.org/doi/10.3171/2014.12.FOCUS14748
"...the authors of this study set out to investigate whether chloroquine (CQ) analogs, in particular clinically established antimalaria drugs, would also be able to exert antitumor properties, with a specific focus on glioma cells.
...the authors treated different glioma cell lines with quinine (QN), quinacrine (QNX), mefloquine (MFQ), and hydroxychloroquine (HCQ) and investigated endoplasmic reticulum (ER) stress–induced cell death, autophagy, and cell death.
All agents blocked cellular autophagy and exerted cytotoxic effects on drug-sensitive and drug-resistant glioma cells with varying degrees of potency (QNX > MFQ > HCQ > CQ > QN)."
Thus, it follows from the study that cloroquine (CQ) shows a weak effect, even lower, that hydroxychloroquine (HCQ) (?!) Maybe this explains the choice of hydroxychloroquine instead of chloroquine in some tests?
And another quotes from the study:
"Cytotoxicity of QBAs for Glioma Cells:
To determine whether other quinoline-based antimalarial (QBA) compounds could mimic the cytotoxic effects of CQ in glioma cells, we used MFQ and QNX. Results showed that these drugs effectively killed U251 cells at much lower concentrations than CQ."
Blocking Autophagy and Inducing Apoptosis in Glioma Cells:
Based on information that CQ induces apoptosis by blocking autophagy, we analyzed whether the other QBA compounds can function in a similar manner.
Quinacrine, the most potent QBA, not only blocked autophagy, but at 20 μM it completely disrupted U251 cellular functioning, which was evidenced by a high level of PARP cleavage, as well as the absence of CHOP/GADD-153 and LC3B expression.
In Vivo Antitumor Activity:
The TUNEL assay for apoptosis demonstrated a significant increase in the number of TUNEL-positive cells in QNX- and QN-> MFQ-> CQ-treated tumors, as compared with untreated controls."
There are also many reports of another inhibitor of autophagy - 3-methyladenine (3-MA).
___________________________________
Since many people here take chloroquine, I would like to discuss the possibility of enhancing its effect. While I see there are the following options:
chloroquine + cimetidine
"Cimetidine pre-treatment caused a 53% decrease in the clearance rate of chloroquine, and a 49% increase in the elimination half-life. Cimetidine inhibited the conversion of chloroquine to monodesethylchloroquine in terms of reductions in the AUC, Cmax, and urinary excretion of monodesethylchloroquine. The serum Cmax of chloroquine was increased by approximately 30% in the cimetidine pre-treated group."
The downside is that since there are many medicines in the cocktail, numerous unpredictable interactions with cimetidine are possible.
increase in the dose of Chloroquine
Instead of using cimetidine, can it be easier to increase the dose of Chloroquine? The standard is 250 mg / day.
chloroquine + hypoxia-inducing agents
2017 https://www.ncbi.nlm.nih.gov/pubmed/28797031
"This work shows that inhibition of autophagy is a promising strategy against GBM and identifies ATG9 as a novel target in hypoxia-induced autophagy. Combination with hypoxia-inducing agents may provide benefit by allowing to decrease the effective dose of autophagy inhibitors."
What hypoxia-inducing agents are they talking about?
___________________________________
I also found several preliminary studies on the synergy of chloroquine and other drugs. It is interesting to study more ..
Dihydroartemisinin + Сhloroquine
2017 https://www.ncbi.nlm.nih.gov/pubmed/29033794
Dihydroartemisinin Exerts Anti-Tumor Activity by Inducing Mitochondrion and Endoplasmic Reticulum Apoptosis and Autophagic Cell Death in Human Glioblastoma Cells.
"Co-treatment with chloroquine (CQ) significantly induced the above effects. Furthermore, ER stress and mitochondrial dysfunction were involved in the dihydroartemisinin-induced autophagy."
Asparaginase + Сhloroquine
2017 https://www.ncbi.nlm.nih.gov/pubmed/29207624
"combination treatment with autophagy inhibitor CQ significantly enhanced anti-glioblastoma efficacy of asparaginase in U87MG cell xenograft model."
Sorafenib + Сhloroquine
2016 https://www.ncbi.nlm.nih.gov/pubmed/26971793
"we combined sorafenib treatment in GBM cells (U373 and LN229) and tumors with the autophagy inhibitor chloroquine. We found that blockage of autophagy further inhibited cell proliferation and migration and induced cell apoptosis in vitro and in vivo. These findings suggest the possibility of combination treatment with sorafenib and autophagy inhibitors for GBM."
