daily doses up to 400 mg of HCQ or 250 mg CQ for several years are considered to carry an acceptable risk for CQ-induced retinopathies, with the exception of individuals of short stature
chronic CQ or HCQ therapy be monitored through regular ophthalmic examinations (3–6 month intervals), full blood counts and blood glucose level checks
long-term HCQ exposure, skeletal muscle function and tendon reflexes should be monitored for weakness
both CQ and HCQ, specific caution is advised in patients suffering from impaired hepatic function (especially when associated with cirrhosis), porphyria, renal disease, epilepsy, psoriasis, glucose-6-phosphate dehydrogenase deficiency and known hypersensitivity to 4-aminoquinoline compounds
CQ and HCQ can effectively increase the efficacy of various anti-cancer drugs
CQ can prevent the entrapment of protonated chemotherapeutic drugs by buffering the extracellular tumour environment and intracellular acidic spaces
This study recommends an adjuvant HCQ dose of 600 mg, twice daily.
HCQ addition was shown to produce metabolic stress in the tumours
HCQ (400 mg/day)
important effects of CQ and HCQ on the tumour microenvironment
The main and most studied anti-cancer effect of CQ and HCQ is the inhibition of autophagy
the expression levels of TLR9 are higher in hepatocellular carcinoma, oesophageal, lung, breast, gastric and prostate cancer cells as compared with adjacent noncancerous cells, and high expression is often linked with poor prognosis
TLR9-mediated activation of the NF-κB signalling pathway and the associated enhanced expression of matrix metalloproteinase-2 (MMP-2), MMP-7 and cyclo-oxygenase 2 mRNA
HCQ can activate caspase-3 and modulate the Bcl-2/Bax ratio inducing apoptosis in CLL, B-cell CLL and glioblastoma cells
In triple-negative breast cancer, CQ was shown to eliminate cancer stem cells through reduction of the expression of Janus-activated kinase 2 and DNA methyl transferase 1 [106] or through induction of mitochondrial dysfunction, subsequently causing oxidative DNA damage and impaired repair of double-stranded DNA breaks
CQ or HCQ would be considered for use in combination with immunomodulation anti-cancer therapies
Therapies used in combination with CQ or HCQ include chemotherapeutic drugs, tyrosine kinase inhibitors, various monoclonal antibodies, hormone therapies and radiotherapy
Most studies hypothesise that CQ and HCQ could increase the efficacy of other anti-cancer drugs by blocking pro-survival autophagy.
daily doses between 400 and 1200 mg for HCQ are safe and well tolerated, but two studies identified 600-mg HCQ daily as the MTD
HCQ is often administered twice daily to limit plasma fluctuations and toxicity
metabolic activity, oxygen transport, and DNA synthesis
Iron is found in the human body in the form of haemoglobin in red blood cells and growing erythroid cells.
macrophages contain considerable quantities of iron
iron is taken up by the majority of cells in the form of a transferrin (Tf)-Fe(III) complex that binds to the cell surface receptor transferrin receptor 1 (TfR1)
excess iron is retained in the liver cells
the endosomal six transmembrane epithelial antigen of the prostate 3 (STEAP3) reduces Fe(III) (ferric ion) to Fe(II) (ferrous ion), which is subsequently transferred across the endosomal membrane by divalent metal transporter 1 (DMT1)
labile iron pool (LIP)
LIP is toxic to the cells owing to the production of massive amounts of ROS.
DHA is quickly converted to Vit-C within the cell, by interacting with reduced glutathione (GSH) [45,46,47]. NADPH then recycles the oxidized glutathione (glutathione disulfide (GSSG)) and converts it back into GSH
Fe(II) catalyzes the formation of OH• and OH− during the interaction between H2O2 and O2•− (Haber–Weiss reaction)
Ascorbate can efficiently reduce free iron, thus recycling the cellular Fe(II)/Fe(III) to produce more OH• from H2O2 than can be generated during the Fenton reaction, which ultimately leads to lipid, protein, and DNA oxidation
Vit-C-stimulated iron absorption
reduce cellular iron efflux
high-dose Vit-C may elevate cellular LIP concentrations
ascorbate enhanced cancer cell LIP specifically by generating H2O2
Vit-C produces H2O2 extracellularly, which in turn inhibits tumor cells immediately
tumor cells have a need for readily available Fe(II) to survive and proliferate.
Tf has been recognized to sequester most labile Fe(II) in vivo
Asc•− and H2O2 were generated in vivo upon i.v Vit-C administration of around 0.5 g/kg of body weight and that the generation was Vit-C-dose reliant
free irons, especially Fe(II), increase Vit-C autoxidation, leading to H2O2 production
iron metabolism is altered in malignancies
increase in the expression of various iron-intake pathways or the downregulation of iron exporter proteins and storage pathways
Fe(II) ion in breast cancer cells is almost double that in normal breast tissues
macrophages in the cancer microenvironment have been revealed to increase iron shedding
Advanced breast tumor patients had substantially greater Fe(II) levels in their blood than the control groups without the disease
increased the amount of LIP inside the cells through transferrin receptor (TfR)
Warburg effect, or metabolic reprogramming,
Warburg effect is aided by KRAS or BRAF mutations
Vit-C is supplied, it oxidizes to DHA, and then is readily transported by GLUT-1 in mutant cells of KRAS or BRAF competing with glucose [46]. DHA is quickly converted into ascorbate inside the cell by NADPH and GSH [46,107]. This decrease reduces the concentration of cytosolic antioxidants and raises the intracellular ROS amounts
ROS activates poly (ADP-ribose) polymerase (PARP), which depletes NAD+ (a critical co-factor of GAPDH); thus, further reducing the GAPDH associated with a multifaceted metabolic rewiring
Hindering GAPDH can result in an “energy crisis”, due to the decrease in ATP production
high-dose Vit-C recruited metabolites and increased the enzymatic activity in the pentose phosphate pathway (PPP), blocked the tri-carboxylic acid (TCA) cycle, and increased oxygen uptake, disrupting the intracellular metabolic balance and resulting in irreversible cell death, due to an energy crisis
mega-dose Vit-C influences energy metabolism by producing tremendous amounts of H2O2
Due to its great volatility at neutral pH [76], bolus therapy with mega-dose DHA has only transitory effects on tumor cells, both in vitro and in vivo.
pharmacological concentrations of AA can sensitize cancer cells to chemotherapy, enhancing its antineoplastic effect
synergistic effect with conventional chemotherapeutic drugs is a fact already reported, in various types of cancer, by numerous authors, namely in pancreatic (Espey et al., 2011), prostate (Gilloteaux et al., 2014), lung (Lee et al., 2017), breast (Kurbacher et al., 1996; Wu et al., 2017) and ovarian (Ma et al., 2014) cancers.
chemosensitizing effect of vitamin C has already been proven by several authors in various types of cancer
intravenous pharmacological concentrations, may not only potentiate the effects of conventional chemotherapy, but also improve the quality of life of cancer patients
AA reinforced the anti-proliferative activity of 5-FU
Combined treatment induced a reduction of 11.5% and 43% in cell viability compared with AA or Iri therapies, respectively, emphasizing the synergistic effect
cytotoxic effect occurred with treatment with Iri alone, but also this effect was further potentiated by the presence of AA.
association of AA with Oxa showed very promising results, considering that a synergistic effect was demonstrated, in almost all conditions
AA and Oxa seem to act synergistically by the activation of the intrinsic pathway of apoptosis, translated on the statistically significant increase of the ratio between BAX and BCL-2 proteins, which in turn is associated with a decrease of Δψm