Excellent work by Prof de Groot of Essen, indicated by adding exogenous xanthine oxidase ( XO) in hepatoma cells, hydrogen peroxide was produced to destroy the hepatoma cells
NO from eNOS in cancer cells can travel through membranes and over long distances in the body
NO also is co linked to VEGF which in turn increases the antiapoptotic gene bcl-2
The other important influence of NO is in its inhibition of the proapoptoic caspases cascade. This in turn protects the cells from intracellular preprogrammed death.
nitric oxide in immune suppression in relation to oxygen radicals is its inhibitory effect on the binding of leukocytes (PMN) at the endothelial surface
Inhibition of inducible Nitric Oxide Synthase (iNOS)
NO from the tumor cells actually suppresses the iNOS, and in addition it reduces oxygen radicals to stop the formation of peroxynitrite in these cells. But NO is not the only inhibitor of iNOS in cancer.
Spermine and spermidine, from the rate limiting enzyme for DNA synthases, ODC, also inhibit iNOS
tolerance in the immune system that decreases the immune response to antigens on the tumors
Freund’s adjuvant
increase in kinases in these cells which phosphorylate serine, and tyrosine
responsible for activation of many growth factors and enzymes
phosphorylated amino acids suppress iNOS activity
Hexokinase II
Prostaglandin E2, released from tumor cells is also an inhibitor of iNOS, as well as suppressing the immune system
Th-1 subset of T-cells. These cells are responsible for anti-viral and anti-cancer activities, via their cytokine production including Interleukin-2, (IL-2), and Interleukin-12 which stimulates T-killer cell replication and further activation and release of tumor fighting cytokines.
Th1 cells stimulate NK and other tumor fighting macrophages via IL-2 and IL-12; In contrast, Th2, which is stimulated in allergies and parasitic infections, produce IL-4 and IL-10. IL-4 and IL-10 inhibit TH-1 activation and the histamine released from mast cell degranulation upregulates T suppressor cells to further immune suppression.
Th-2 subset of lymphocytes, on the other hand are activated in allergies and parasitic infections to release Interleukin-4 and Interleukin-10
These have respectively inhibitory effects on iNOS and lymphocyte Th-1 activation
Mast cells contain histamine which when released increases the T suppressor cells, to lower the immune system and also acts directly on many tumor Histamine receptors to stimulate tumor growth
Tumor cells release IL-10, and this is thought to be one of the important areas of Th-1 suppression in cancer patients
IL-10 is also increased in cancer causing viral diseases such as HIV, HBV, HCV, and EBV
IL-10 is also a central regulator of cyclooxygenase-2 expression and prostaglandin production in tumor cells stimulating their angiogenesis and NO production
nitric oxide in tumor cells even prevents the activation of caspases responsible for apoptosis
NO produced by cancer cells inhibits proapoptotic pathways such as the caspases.
early stages of carcinogenesis, which we call tumor promotion, one needs a strong immune system, and fewer oxygen radicals to prevent mutations but still enough to destroy the tumor cells should they develop
later stages of cancer development, the oxygen radicals are decreased around the tumors and in the tumor cells themselves, and the entire cancer fighting Th-1 cell replication and movement are suppressed. The results are a decrease in direct toxicity and apoptosis, which is prevented by NO, a suppression of the macrophage and leukocyte toxicity and finally, a suppression of the T-cell induced tumor toxicity
cGMP is increased by NO
NO in cancer is its ability to increase platelet-tumor cell aggregates, which enhances metastases
the greater the malignancies and the greater the metastatic potential of these tumors
The greater the NO production in many types of tumors,
gynecological
elevated lactic acid which neutralizes the toxicity and activity of Lymphocyte immune response and mobility
The lactic acid is also feeding fungi around tumors and that leads to elevated histamine which increases T-suppressor cells. Histamine alone stimulates many tumor cells.
The warburg effect in cancer cells results in the increase in local lactic acid production which suppresses lymphocyte activity and toxicity as well as stimulates histamine production with further stimulates tumor cell growth.
T-regulatory cells (formerly,T suppressor cells) down regulate the activity of Natural killer cells
last but not least, the Lactic acid from tumor cells and acidic diets shifts the lymphocyte activity to reduce its efficacy against cancer cells and pathogens in addition to altering the bacteria of the intestinal tract.
intestinal tract bacteria in cancer cells release sterols that suppress the immune system and down regulate anticancer activity from lymphocytes.
In addition to the lactic acid, adenosine is also released from tumors. Through IL-10, adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state
Adenosine up regulates the PD1 receptor in T-1 Lymphocytes and inhibits their activity
Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells
Adenosine appears to up-regulate the PD1 receptor in T-1 Lymphocytes and inhibits the immune system further
Mast cells with their release of histamine lower the immune system and also stimulate tumor growth and activate the metalloproteinases involved in angiogenesis and metastases
COX 2 inhibitors or all trans-retinoic acid
Cimetidine, an antihistamine has been actually shown to increase in apoptosis in MDSC via a separate mechanism than the antihistamine effect
interleukin-8 (IL-8), a chemokine related to invasion and angiogenesis
In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNF-alpha)
these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-alpha-induced up-regulation of IL-8 via nuclear factor-kappaB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target
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