Chloroquine commonly induces hormetic dose responses

Calabrese, Edward J.; Hanekamp, Jaap C.; Hanekamp, Yannic N.; Kapoor, Rachna; Dhawan, Gaurav; Agathokleous, Evgenios

doi:10.1016/j.scitotenv.2020.142436

Cited by 10 publications

(9 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At sub-therapeutic dosing in our study, mefloquine treatment decreased lysosomal pH and increased proteolysis but, conversely, lysosomal accumulation increased over baseline. These effects on lysosomal pH and activity resemble a biphasic dose response (hormesis) described previously for chloroquine and its derivatives and may explain the varied outcomes in the treatment of COVID-19 patients with lysosomotropic drugs (Calabrese et al, 2021;Moore, 2020).…”

Section: Discussionsupporting

confidence: 62%

Endo-Lysosome-Targeted Nanoparticle Delivery of Antiviral Therapy for Coronavirus Infections

Petcherski,

Tingley,

Martin

et al. 2023

Preprint

View full text Add to dashboard Cite

SARS-CoV-2 can infect cells through endocytic uptake, a process which can be targeted by inhibition of lysosomal proteases. However, clinically this approach fared poorly with an oral regimen of hydroxychloroquine that was accompanied by significant toxicity due to off-target effects. We rationalized that an organelle-targeted approach will avoid toxicity while increasing the concentration of the drug at the target. Here we describe a lysosome-targeted, mefloquine-loaded poly(glycerol monostearate-co-ε-caprolactone) nanoparticle (MFQ-NP) for pulmonary delivery via inhalation. Mefloquine is a more effective inhibitor of viral endocytosis than hydroxychloroquine in cellular models of COVID-19. MFQ-NPs are less toxic than molecular mefloquine, 100-150 nm in diameter, and possess a negative surface charge which facilitates uptake via endocytosis allowing inhibition of lysosomal proteases. MFQ-NPs inhibit coronavirus infection in mouse MHV-A59 and human OC43 coronavirus model systems and inhibit SARS-CoV-2-WA1 and its Omicron variant in a human lung epithelium model. This study demonstrates that organelle-targeted delivery is an effective means to inhibit viral infection.

show abstract

Section: Discussionsupporting

confidence: 62%

Endo-Lysosome-Targeted Nanoparticle Delivery of Antiviral Therapy for Coronavirus Infections

Petcherski,

Tingley,

Martin

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…It was shown that IsoLQ pretreatment of a kidney cell line induced ER stress-mediated hormesis [ 60 ]. Other agents inducing a hormetic dose response are chloroquine [ 61 ] and green tea with its principal constituent (-)-epigallocatechin-3-gallate (EGCG) [ 62 ]. Both of the agents have been demonstrated to enhance a spectrum of neuroprotective responses.…”

Section: Discussionmentioning

confidence: 99%

Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications

Schirrmacher¹

2021

Biomedicines

View full text Add to dashboard Cite

A dose-response relationship to stressors, according to the hormesis theory, is characterized by low-dose stimulation and high-dose inhibition. It is non-linear with a low-dose optimum. Stress responses by cells lead to adapted vitality and fitness. Physical stress can be exerted through heat, radiation, or physical exercise. Chemical stressors include reactive species from oxygen (ROS), nitrogen (RNS), and carbon (RCS), carcinogens, elements, such as lithium (Li) and silicon (Si), and metals, such as silver (Ag), cadmium (Cd), and lead (Pb). Anthropogenic chemicals are agrochemicals (phytotoxins, herbicides), industrial chemicals, and pharmaceuticals. Biochemical stress can be exerted through toxins, medical drugs (e.g., cytostatics, psychopharmaceuticals, non-steroidal inhibitors of inflammation), and through fasting (dietary restriction). Key-lock interactions between enzymes and substrates, antigens and antibodies, antigen-presenting cells, and cognate T cells are the basics of biology, biochemistry, and immunology. Their rules do not obey linear dose-response relationships. The review provides examples of biologic stressors: oncolytic viruses (e.g., immuno-virotherapy of cancer) and hormones (e.g., melatonin, stress hormones). Molecular mechanisms of cellular stress adaptation involve the protein quality control system (PQS) and homeostasis of proteasome, endoplasmic reticulum, and mitochondria. Important components are transcription factors (e.g., Nrf2), micro-RNAs, heat shock proteins, ionic calcium, and enzymes (e.g., glutathion redox enzymes, DNA methyltransferases, and DNA repair enzymes). Cellular growth control, intercellular communication, and resistance to stress from microbial infections involve growth factors, cytokines, chemokines, interferons, and their respective receptors. The effects of hormesis during evolution are multifarious: cell protection and survival, evolutionary flexibility, and epigenetic memory. According to the hormesis theory, this is true for the entire biosphere, e.g., archaia, bacteria, fungi, plants, and the animal kingdoms.

show abstract

“…Interestingly, hepatic human cells (HEK 293) were the most sensitive to CLQ treatment, both in high and low concentrations, showing two IC 50 values to the same treatment (see Table ). This hormetic behavior, characterized by a biphasic dose response, has already been documented for CLQ treatments . In addition to the high sensitivity of human cells, it has been reported in the literature that CLQ has a tumor-promoting effect on breast cancer cells .…”

Section: Results and Discussionmentioning

confidence: 60%

“…This hormetic behavior, characterized by a biphasic dose response, has already been documented for CLQ treatments. 60 In addition to the high sensitivity of human cells, it has been reported in the literature that CLQ has a tumor-promoting effect on breast cancer cells. 61 Our results, in addition to literature reports and the WHO recommendations, reinforce the idea that these molecules should be further studied.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

New Insights into the Mechanism of Action of the Drug Chloroquine: Direct Interaction with DNA and Cytotoxicity

Rocha

2022

J. Phys. Chem. B

View full text Add to dashboard Cite

Chloroquine (CLQ) and hydroxychloroquine (HCLQ) are compounds largely employed in the treatment of various human diseases for decades. Nevertheless, a number of intrinsic details concerning their mechanisms of action, especially at the molecular level, are still unknown or have presented controversial results in the literature. Using optical tweezers, here, we investigate at the single-molecule level the molecular mechanism of action of the drug CLQ in its intrinsic interaction with the double-stranded (ds)DNA molecule, one of its targets inside cells, determining the binding modes and the physicochemical (binding) parameters of the interaction. In particular, we show that the ionic strength of the surrounding medium strongly influences such interaction, changing even the main binding mode. In addition, the cytotoxicity of CLQ against three different cell lines was also investigated here, allowing one to evaluate and compare the effect of the drug on the cell viability. In particular, we show that CLQ is highly cytotoxic at a very low (a few micromolar) concentration range for all cell lines tested. These results were rigorously compared to the equivalent ones obtained for the closely related compound hydroxychloroquine (HCLQ), allowing a critical comparison between the action of these drugs at the molecular and cellular levels.

show abstract

Chloroquine commonly induces hormetic dose responses

Cited by 10 publications

References 66 publications

Endo-Lysosome-Targeted Nanoparticle Delivery of Antiviral Therapy for Coronavirus Infections

Endo-Lysosome-Targeted Nanoparticle Delivery of Antiviral Therapy for Coronavirus Infections

Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications

New Insights into the Mechanism of Action of the Drug Chloroquine: Direct Interaction with DNA and Cytotoxicity

Contact Info

Product

Resources

About