A Silver Bullet to Kill Cancer

Background

Silver was the most important antimicrobial agent available before the introduction of antibiotics. The natural antibacterial action of silver has been known already since antiquity. The Romans used the effects of the silver for water purification. It is likely that silver nitrate also was used medically because it was mentioned in a pharmacopeia published in Rome in 69 B.C.E. Herodotus, the Father of History, accounts that no Persian king, including Cirrus, would drink water that was not transported in silver containers, which kept the water fresh for years (Ref.1, Ref.2).

In line with this, during the past decades it has been scientifically demonstrated that silver (and silver nano-particles):

• has anti-bacterial properties against a range of both Gram-negative (e.g. Acinetobacter, Escherichia, Pseudomonas, Salmonella and Vibrio) and Gram-positive bacteria (e.g. Bacillus, Clostridium, Enterococcus, Listeria, Staphylococcus and Streptococcus) (Ref.1, Ref.2, Ref.3, Ref.4)
• kills fungi such as Aspergillus niger, Candida albicans (Ref.) and Saccharomyces cerevisia, (Ref.1, Ref.2) and
• has antiviral activity against e.g. hepatitis B virus (Ref.), HIV-1 (Ref.), syncytial virus (Ref.) and others (Ref.)

As a result, in medical care nanosilver has been used, for example, as an antibacterial agent in wound dressings such as bandages to protect patients with severe burning against infections. Researchers have even thought about developing techniques to coat glass with a layer of silver ions that can prevent growth of pathogenic bacteria including Escherichia coli, Salmonella typhimurium and Campylobacter jejuni (Ref.).

Beyond the professional use, silver (in the form of nano-particles) is used as home remedy. Silver nano-particles are made up of extremely small particles of silver, with lengths of 1–100 nm. It may sound complicated, but nano-particles can even be made at home. One of the first reports on making silver nano-particles goes back to 1889 (Ref.). However, silver nano-particles are also commercially available at online stores as silver nano-particle solution.

Besides their antimicrobial, antifungal, and antiviral properties, silver nano-particles have also been shown to posed anti cancer potential. Indeed, scientists demonstrated in laboratory experiments that silver nano-particles, when used alone or in combination with conventional therapies (including chemo- and radio-therapy) can kill various cancer cells, such as:

• Pancreatic cancer (Ref.1, Ref.2, Ref.3)
• Cervical cancer (Ref.)
• Ovarian cancer (Ref.)
• Breast cancer (Ref.1, Ref.2)
• Glioma (Ref.)
• Lung cancer (Ref.)
• Leukemia (Ref.)
• Lymphoma (Ref.)
• Hepatocellular carcinom (Ref.1, Ref.2, Ref.3)
• Head and neck squamous cell cancer (see below)

Nevertheless, due to the mechanism of action, silver nanoparticles are expected to act against most type of cancers, both directly and indirectly by e.g. inhibiting the formation of new blood vessels as discussed in the “Anti Cancer Mechanism” sections below, and killing intratumoral bacteria.

Indeed, a very important mechanism through which silver treatments helps fight cancer is related to the intratumoral bacteria. One of the most recently identified causes of resistance to cancer therapeutics involves intratumoral bacteria (Ref.1, Ref.2). Hypoxia and necrosis are common in tumor tissues due to their fast growth, providing the perfect environment in which bacteria can easily enter and successfully colonize. This is not only theory. It has been indeed shown (and published in Nature journal) that when tumours are colonise by bacteria, their resistance to chemotherapy such as Gemcitabine strongly increases (Ref.). All these aspects are nicely discussed in this very recent (2019) paper, entitled “Silver-Nanoparticle-Mediated Therapies in the Treatment of Pancreatic Cancer“. Another paper, also recently published in one of the most well known journals, Science, also shown the role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug Gemcitabine (Ref.). Based on this important research, one could argue that it is a must to use anti bacterial treatments (such as Silver solution and/or others) before, during and after conventional treatments, in order to increase the chance of a successful treatment outcome.

Successful Case Reports on Anti-Cancer Action in Humans

There are many anecdotal reports online, claiming complete remission of various cancers after patients used silver nano-particles as home remedies. While there is science to support that potential, it may be hard to believe that using such a simple solution it is possible to obtain complete remissions, given the fact that cancer is still one of the major challenges of humanity. This is why, next to the scientific evidence in the laboratory and anecdotal reports, I think it’s always important to also have scientific reports published by experts demonstrating the potential. This helps us to better select value from the noise. 

Fortunately, with the help of a visitor of this website we recently became aware of a recent case report where a 78‐year old man. The case was reported at the end of 2018 by the MDs at the UT Southwestern Medical Center, Dallas, Texas, USA. With this, I would like to thank you to the team of MDs for being so open minded and taking the time to consolidate and share this amazing case report. The patient reported in this article had an aggressive cancer that was not responding to conventional treatment while cancer was progressing and new metastasis were fund at the liver and lungs. The patient was recommended to transition to hospice as he was found to be a poor candidate for salvage therapy given his decline in functional capacity and multiple recurrences despite aggressive anticancer therapy.

However, the patient manufactured his own silver nano-particles using online instructions (discussed in the “Source” section). After 3 months of using this solutions the patient experienced significant clinical improvements, and showed complete disappearance of all pulmonary and liver metastases as well as of previously seen nodes in the neck. The authors further state that: this recovery and complete resolution of cancer at all sites persisted for 36 months and is ongoing. (Ref.).

This is an amazing response, and given the accessibility, low cost, ease of implementation, and good knowledge on the safety profile of using silver nano-particles, it makes sense to be seriously considered by any cancer patient that may not have any other treatment option left.

Like with all treatments discussed, I would not use this as a stand alone treatment approach but when possible add it next to other conventional or alternative treatments as a part of a more comprehensive treatment strategy.

The published and well documented case report can be accessed here: 

Activity and pharmacology of homemade silver nanoparticles in refractory metastatic head and neck squamous cell cancer

Anti Cancer Mechanisms

• ROS generations: Trigger mitochondria-mediated apoptosis by increasing ROS production and decreasing ATP generation: cell death is initiated by entry of AgNPs into the cells, which then triggers ROS production, LDH leakage, increase of pro-oxidants, and decrease of antioxidants, which leads to cytotoxicity. Altering of mitochondrial membrane potential (MMP) subsequently results in the release of pro-apoptotic mitochondrial proteins into the cytosol. This activates caspase-dependent processes culminating in cell death. Loss of MMP hampers mitochondrial function, which triggers a bio-energetic crisis due to loss of ATP. Depending on the intensity of the mitochondrial insult, the cell can undergo apoptosis, necrosis, and/or autophagic cell death, such as accumulation of autophagosomes (Ref.)
  .
• Anti-angiogenesis (new blood vessels formation inhibitor): While going through a case report of a lady who ingested an extreme amount of silver particels experiencing argyria, I found interesting that all her blood analysis came out well, with the exception of the serum silver concentration that was 381 ng/ml (reference value <15 ng/ml) while her serum copper level was 24.8 mg/dl (normal range 70.0–155.0 mg/dl), and serum ceruloplasmin was 9.0 mg/dl (normal range 17.9–53.3 mg/dl). As we discussed here, Copper is essential for angiogenesis and tumor growth and Copper depleting treatments can be effective anti cancer treatments (Ref.). Indeed, after searching through the literature, I found more case reports where high ingestion of silver nanoparticles leads to copper and caeruloplasmin deficiency (Ref.1, Ref.2). This is why silver solutions may also be effective against ascites (Ref.).
  .
  Here I also found a paper reporting that Silver nanoparticles can act as an angiogenessis inhibitor, but the authors did not connect that with silver influence on copper metabolism but with HIF-1 modulation (Ref.). Digging further in literature we find that indeed it is known that Silver inhibits Copper transport (Ref.).
  .
  This is a similar effect as that of Tetrathiomolybdate https://www.cancertreatmentsresearch.com/tetrathiomolybdate-tm/, a Copper depleting substance with known anticancer effects. Actually Copper and Silver use the same transporter (CTR1 or copper transporter 1) when is absorbed in the body. And when used in higher amounts Silver is known to inhibit that https://www.sciencedirect.com/science/article/pii/S0946672X10000106 In turn, CTR1 silencing inhibits Angiogenesis by limiting copper entry into the cells https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071982
  .
• Autophagy disruption (Ref.)
  .
• Killing intratumoral bacteria – see explanation and references at the end of the Background section, above
  .
• Multi Drug Resistance (MDR1) inhibition to increase/enable effectiveness of chemotherapy (Ref.) – for this purpose, larger nano particles (about 75nm) are more efficient than the small ones
  .
• Inducing Endoplasmic reticulum (ER) stress (Ref.)

Toxicity and Side Effects

Research suggests that the generation of ROS is the mechanism underlying the cytotoxicity of silver nanoparticles (Ref.).

Silver was cleared from most organs after 8 weeks, but there is a longer retention of silver in brain and testis that should be considered in a risk assessment of silver nanoparticles (Ref.). Indeed, it has been shown that folloing the administration of silver nanoparticles, the anti-oxidant production inside the cells increases (via the activation of Nrf2 pathway – I discussed this pathway and its modulators sometimes ago here) (Ref.). On this line, if a patient uses high doses of Silver nanoparticles, he/she should be pay attention to the other pro-oxidant treatments used (such as chemo) since using more proxidant treatments at the same time may increase the risk of side effects. 

Given the main mechanism leading to side effects indicated in the literature, I would always make sure to have strong anti oxidants at home, such as NAC (supplement available on-line) and use it if side effects are present during the use of silver nanoparticles.

Supplementation with Selenium or Vitamin E has been shown to increase the maximum acceptable exposure to silver (Ref.).

There are case reports where that were over exposed to silver, or to silver dust have experienced dramatic symptom of argyria where the skin turns purple or purple-grey. For example, a case of generalized argyria after ingestion of colloidal silver solution has been reported in 2009 (Ref.). The patient stated that she had ingested 1 L of colloidal silver solution daily and had sprayed it on her face and scalp for approximately 16 months as a traditional remedy. She used this preparation to promote health. She prepared the solution with a colloidal silver solution generator, which produced the solution by electrolyzation of silver and which was purchased from an alternative medicine company. Silver concentrations in two samples (one was a recent sample and the other was prepared several months ago) of the colloidal silver solution which she had taken were measured by ICP optical emission spectroscopy (ICP-OES), 38.26 and 29.12 ppm, respectively. 1L/day of such a high concentration is indeed huge.

Argyria generally does not have a serious complications associated with it with the exception of cosmetic damage. However, patients over using silver nanoparticles such as the example above saw copper level was 24.8 mg/dl (normal range 70.0–155.0 mg/dl), and serum ceruloplasmin was 9.0 mg/dl (normal range 17.9–53.3 mg/dl). While this can be good for anti cancer purpose, making sure that we maintain a safe level of coper in the body is important. The safe levels of Copper and Ceruloplamsin were discussed previously on this website here. Blood tests can be done from time to time to make sure these are in a safe range. Once you have argyria, you may not be able to reverse the effects. 

Therefore, like with everything in life, too much of something is not good. So the questions is what are the safe levels?

Although according to on-line discussions people seem to use much higher doses, the current guidelines for oral silver exposure is 5 ug/kg/d with a critical dose estimated at 14 ug/kg/d for the average person (Ref.).

During 2013, in USA, a study was conducted looking at human exposure (60 healthy subjects) to commercial nanoscale silver colloid in a single-blind, controlled, cross-over, intent-to-treat design. Two different commercial silver nano-particle solutions were used, one with particle sizes between 5 – 10nm (10ppm solution) and one with particles between 25-40 nm (32 ppm solution). With the 10ppm solution subjects were dosed for 3, 7 or 14 days (100µg/day – equivalent to 1.4µg/kg body weight – assuming 70kg adult), while for the 32 ppm solution all subjects were dosed for 14 days (480µg/day – equivalent to 6.8µg/kg bw). Subjects underwent metabolic, blood counts, urinalysis, sputum induction and chest and abdomen magnetic resonance imaging. Silver serum and urine levels were also determined. The authors reported that no morphological changes were detected in the lungs, heart or abdominal organs and that no significant changes were noted in pulmonary reactive oxygen species or pro-inflammatory cytokine generation. They saw no clinically important changes in human metabolic, haematologic, urine, physical findings or imaging morphology. (Ref.) Therefore 6.8µg/kg dose seems to be a safe dose. Very roughly, this would 100x lower dose compared to the case above experiencing argyria.

Note: because ingestion of Silver reduces Copper which is essential for the creation of new blood vessels, it is best that pregnant women avoid using Silver nanoparticles.

Pharmacokinetics

The routes via which silver nano-particles gain entry into the body of an organism consist of oral ingestion, physical contact (through skin lesions or abrasions), pulmonary inhalation, and intravenous/intraperitoneal injection for either diagnostic or therapeutic purposes.  Evidence from animal studies has shown that silver nano-particles are capable of being distributed to most organs following oral exposure (Ref.1, Ref.2).

Studies in animals shown that regardless of the silver nano-particle size, the silver content in most tissues gradually decreased during the 4-month recovery period, indicating tissue clearance of the accumulated silver. The exceptions were the silver concentrations in the brain and testes, which did not clear well, even after the 4-month recovery period, indicating an obstruction in transporting the accumulated silver out of these tissues. The same study indicated that the size of the silver nano-particles did not affect silver tissue distribution (Ref.).  Absorbed silver deposited in skin has a much longer half-life.  Excretion of silver is primarily via fecal elimination with active biliary excretion. Previous studies have confirmed that even inhaled silver is eliminated primarily in the feces (Ref.).

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Source:

According to this work (Ref.), 5nm particles succeeded to kill Candida A. while 100nm particles did not. In lab experiments, the size of nano-particles influences the binding and activation of membrane receptors and subsequent protein expression in cancer cells (Ref.). Therefore, from an activity point of view size matters. Also, the patient discussed above used 3nm and 12nm particles. So I would make sure that whatever source I use, the average particle size is below 10nm, preferably around 5nm.

One other aspect that should be discussed is related to the fact that most silver solutions contain both silver particles (clusters of atoms) and silver ions (silver atoms that have lost an electron). Here is a discussion on this subjects. Various manufacturers have tried to differentiate themselves via the quality of the nano particles they are producing, containing less silver ions and more nano-particles. However the patient in the case report above, manufactured his silver solution at home and it worked – I believe his solution contained a lot of silver ions (Ag+) and very little amount of nano-particles. He measured 0.09‐0.15 ppm, i.e. 90ug/L to 150ug/L using a water tester. What this water tester measures is silver ions that are released in the water as they raise the electrical conductivity of the water. In fact, it seems that good quality, commercially bottled colloidal silver is about 85% ionic and 15% particles (Ref.).

Note: I actually have doubts that the patient discussed above measured 0.09 to 0.15 ppm. The accuracy of the water testers available online is such that it can measure minimum 1 ppm and not o.o1 ppm. These devices, usually have a display that shows 3 digits (Ref.). So I suspect that the man in the case report above reported to his doctors that he was measuring 009 to 015 ppm as it was displayed, but the MDs noted 0.09 to 0.15 ppm while that was actually 9 to 15ppm. This also makes sense to me given that the time used to create the solution was about an hour. If that is the case, he may have used a dose of up to 25ug/kg/day. If this is true, this dose is above what is considered to be a critical dose estimated at 14 ug/kg/d for the average person (Ref.). Yet, this is inline with doses suggested online, e.g. 3 to 6 ounce/day of 8ppm solution (Ref.) or even more (Ref.). This is my guess and I would like to verify this as soon as possible with the authors, but it would mean that the patient used a dose 100x higher compared to what is stated in the article. Actually, the fact that the patient was using mash cloth to filter out the remaining precipitated silver also indicated that the concentration he was getting was in the range of 10 to 20ppm (see this video to understand what I mean).

Silver ions are also know to have anti-cancer and anti bacterial activity (Ref.). In fact it is even debatable how much of the nano particles are getting into the blood. For example, in this study silver concentrations in the organs were highly correlated to the amount of Ag⁺ in the silver nano-particle suspension, indicating that mainly Ag⁺, and to a much lesser extent silver nano-particles, passed the intestines in the silver nano-particle exposed rats (Ref.). Other study on human subjects concluded that most of the silver detected in the blood was of ionic form with no evidence that intact silver nano-particles are either absorbed into circulation through the human digestive tract, or attached to blood components (e.g., proteins, platelets and cells) (Ref.). On the same line with this, the blood of the patient discussed above was investigated but intact nano-particles were not identified (Ref.).

Therefore, regardless of the source, when using silver solutions, I would want to make sure that the silver solution contains particles <10nm, preferably 5nm. All solutions will most certainly contain both silver nano-particles and silver ions.

Here is a website that explains nicely exactly what I was stating above https://www.colloidalsilver.com.au/Making-CS.html

Commercial: 

There are various brands available online. I have no preferred brand. One such brand was mentioned by Shanti here. I would go for the brands that seem to be for the longest time in the market and that deliver the smallest nano-particles. If no health improvements are seen after using one brand, I would try another one.

Home made version:

According to the case report. the patient discussed above began to manufacture and consume an silver nano-particles solution, with the following method of production:

• Twelve ounces of distilled water is placed in a glass container containing two bars of 99.99% pure silver.
  • one ounce = 29.5735 ml water
  • tap water, mineral water, etc. is not good due to the impurities – any water that becomes cloudy white after the power is applied is not good because as the silver ions are released from the electrodes they will immediately combine with salts, minerals, and other impurities in the tap water to form silver nitrates, chlorides, and other compounds
  • example of silver electrodes available online is here and here and here and here, etc. Other people prefer to buy silver bars as that will certainly be of 99.99% purity as stated by the producer. Here is an example of a supplier but there are many more like this accessible on the web.
• Three 9‐V radio batteries are hooked in series, producing a positive lead at one end and a negative lead at the other, resulting in a total output of 27 V of electricity.
• A current is applied until the metal content of the water measures 0.09‐0.15 ppm using a water tester, and this process averages 1 hour in duration.
  • Please see my remark above in red as I believe the patient created a 9 to 15ppm solution and not 0.09-0.15 ppm
  • As silver ions are released in the water they raise the electrical conductivity of the water, and consequently can be measured (approximately ) with a hand-held meter – No hand-held meter in the world can actually measure PPM, so hand-held PWT and TDS meters are a guide only
  • nano-particles hat may be made up of relatively few, or many thousands of silver atoms. They may be pure silver, or silver oxides, but they are so small they stay permanently suspended within the water and do not settle to the bottom. These particles are not actually made by the generator. They are created in the water as the ions combine (Ref.).
  • Example of water testers that can be bought online: e.g. Ref.1, Ref.2, etc.
• The resulting solution is strained with a mesh cloth to filter out remaining silver precipitate and the product is subsequently stored in a dark glass bottle
  • do not store the silver solution in the refrigerator as it may precipitate – store at room temperature
  • the solution is light sensitive so it’s important to store in a dark glass bottle
  • some people are using coffee filters to filter out the remaining silver precipitate

The nano-particles created had a size distributed of 3nm and 12 nm (Ref.). We can use a cheap laser pointer to verify if we have nano-particles in the solution by using Tyndall Effect (TE) as discussed here (Ref.). According to the Tyndall Effect, if the solution had a Light-Yellow colour it will be at about 1-3ppm, Yellow is 4-6ppm, Deep Yellow 7-9ppm and Amber 10-20ppm.

Here are some websites or Youtube videos describing how to make silver solution at home:

• http://survival-mastery.com/diy/how-to-make-colloidal-silver.html
• https://youtu.be/Acpvp_8gwlw
• https://youtu.be/p0Ucg5hHdb4
• https://www.youtube.com/watch?v=gqVoXSspJ-I
• https://www.quantumbalancing.com/makeyourowncs.htm

Here is an example of a devices that is commercialy available to help create the solution at home: https://www.colloidalsilver.com.au/

Daily Administration Dose

There are different ways to administer silver solution, including topical, inhalation, injection, oral. Here I will discuss the dose used for oral administration.

Because the silver solution measured at home with a water tester and referred to as ppm is not necessary what it is measured by the commercial sources as ppm, I prefer to discuss the dose to be used separately, depending on the source:

Dose reference 1, based on commercials source:

Assuming a 5 – 10nm particles, and a 10ppm (10mg/L) solution from a commercial source, I would want to to use a 1.4µg/kg body weight. If I would have 70kg, I would want to use 100µg/day. For a 10ppm solution containing 10mg/L nano-particles, I would have to use 10ml solution/day that would contain my target dose of a total of 100µg/day. I would chose this dose as it has been found to be safe in a previous study on humans (Ref.). This dose also aligns well with the maximum daily dose of 5 ug/kg body weight, suggested to be used for the average person (Ref.).

However, for fighting active disease, I would tend to explore higher daily dose, as I think this may be too low. 

Dose reference 2, based on home-made version:

According to the case report of the man experiencing complete remission, he ingested 120 mL of the solution daily for 3 months during which time he had significant clinical improvement. The paper indicates that the solution contains 0.09‐0.15 ppm, i.e. 90ug/L to 150ug/L concentration of silver. 120mL/day at 0.15ppm would mean that the patient took maximum 18ug/day. Assuming that the weight of the patient was 70kg, the dose he used was 0.25ug/kg/day. That is very low dose, well below the max daily dose suggested at 5 ug/kg/d (Ref.). 

However, please see my remark above, in red, as I believe the patient created a 9 to 15ppm solution and not 0.09-0.15 ppm. If that is the case, he may have used a dose of up to 25ug/kg/day. If this is true, this dose is above what is considered to be a critical dose estimated at 14 ug/kg/day for the average person (Ref.). Yet, this is inline with doses suggested online, e.g. 3 to 6 ounce/day of 8ppm solution and even higher (Ref.), that is about what the patient used. 

I will try to check with the authors (Ref.) and see if the patient actually used 9 to 15ppm solution.

Until I clarify this point, just following the procedure of making silver nano-particles as described above should lead to the same concentration used by the patient that obtained complete remission. Taking 120ml/day of that should be in-line with the patient that obtained complete remission in 3 months.

Ideas for increased effectiveness:

Combining silver nano-particles with histone deacetylases inhibitors (HDACi) may increase the anti cancer effectiveness (Ref.). Valproic Acid, an FDA approved drug available in most of the countries is such as HDAC inhibitor that is both accessible and relatively easy to implement (Ref.).

Combining silver nano-particles with Salinomycin may be more effective (Ref.).

Other points:

As intestinal flora may also be affected by Silver, we may want to also use probiotics several hours after taking the silver solution. 

References:

History of the medical use of silver https://www.ncbi.nlm.nih.gov/pubmed/19566416

BACKGROUND: Silver has been used extensively throughout recorded history for a variety of medical purposes.

METHODS: A review of the literature in English was undertaken, primarily using PUBMED, to identify the medical uses of silver before the clinical introduction of antibiotics in the 1940s.

RESULTS: Silver has been used for at least six millennia to prevent microbial infections. It has been effective against almost all organisms tested and has been used to treat numerous infections and noninfectious conditions, sometimes with striking success. Silver also has played an important role in the development of radiology and in improving wound healing.

CONCLUSION: Silver was the most important antimicrobial agent available before the introduction of antibiotics.

Silver Products for Medical Indications: Risk-Benefit Assessment https://pdfs.semanticscholar.org/b2d2/03e6164f4e6e81c0c05e7dd72a881d663aae.pdf?_ga=2.5726771.1248551559.1562605712-1281643156.1562605712

Background: Legitimate medicinal use of silver-containing products has dramatically diminished over the last several decades. Recently, however, some manufacturers have begun to enthusiastically promote oral colloidal silver proteins as mineral supplements and for prevention and treatment of many diseases. Indiscriminate use of silver products can lead to toxicity such as argyria. Objective: To assist health care professionals in a risk versus benefit assessment of over-the-counter silver-containing products, we herein examine the following issues: historical uses, chemistry, pharmacology, clinical toxicology, case reports of adverse events in the literature, and the recent promotion of over-the-counter silver products. Other sources of silver exposure (including environmental and dietary) and EPA exposure standards are discussed. A list of currently available silver products is provided for easy reference and screening. Conclusions: We emphasize the lack of established effectiveness and potential toxicity of these products.

Combination Effect of Silver Nanoparticles and Histone Deacetylases Inhibitor in Human Alveolar Basal Epithelial Cells https://www.ncbi.nlm.nih.gov/pubmed/30111752

Although many treatment strategies have been reported for lung disease, the mechanism of combination therapy using silver nanoparticles (AgNPs) and histone deacetylases inhibitors (HDACi) remains unclear. Therefore, innovative treatment strategies are essential for addressing the therapeutic challenges of this highly aggressive lung cancer. AgNPs and HDACi seem to be the best candidates for anticancer therapy because of their anti-proliferative effect in a variety of cancer cells. First, we synthesized AgNPs using wogonin as a reducing and stabilizing agent, following which the synthesized AgNPs were characterized by various analytical techniques.

The synthesized AgNPs exhibited dose- and size-dependent toxicity towards A549 cells. Interestingly, the combination of AgNPs and MS-275 significantly induces apoptosis, which was accompanied by an increased level of reactive oxygen species (ROS); leakage of lactate dehydrogenase (LDH); secretion of TNFα; dysfunction of mitochondria; accumulation autophagosomes; caspase 9/3 activation; up and down regulation of pro-apoptotic genes and anti-apoptotic genes, respectively; and eventually, induced DNA-fragmentation.

Our findings suggest that AgNPs and MS-275 induce cell death in A549 lung cells via the mitochondrial-mediated intrinsic apoptotic pathway. Finally, our data show that the combination of AgNPs and MS-275 is a promising new approach for the treatment of lung cancer and our findings contribute to understanding the potential roles of AgNPs and MS-275 in pulmonary disease. However, further study is warranted to potentiate the use of this combination therapy in cancer therapy trials.

Combination of salinomycin and silver nanoparticles enhances apoptosis and autophagy in human ovarian cancer cells: an effective anticancer therapy https://www.ncbi.nlm.nih.gov/pubmed/27536105

Ovarian cancer is one of the most important malignancies, and the origin, detection, and pathogenesis of epithelial ovarian cancer remain elusive. Although many cancer drugs have been developed to dramatically reduce the size of tumors, most cancers eventually relapse, posing a critical problem to overcome. Hence, it is necessary to identify possible alternative therapeutic approaches to reduce the mortality rate of this devastating disease. To identify alternative approaches, we first synthesized silver nanoparticles (AgNPs) using a novel bacterium called Bacillus clausii. The synthesized AgNPs were homogenous and spherical in shape, with an average size of 16-20 nm, which are known to cause cytotoxicity in various types of human cancer cells, whereas salinomycin (Sal) is able to kill cancer stem cells.

Therefore, we selected both Sal and AgNPs to study their combined effect on apoptosis and autophagy in ovarian cancer cells. The cells treated with either Sal or AgNPs showed a dose-dependent effect with inhibitory concentration (IC)-50 values of 6.0 µM and 8 µg/mL for Sal and AgNPs, respectively. To determine the combination effect, we measured the IC25 values of both Sal and AgNPs (3.0 µM and 4 µg/mL), which showed a more dramatic inhibitory effect on cell viability and cell morphology than either Sal or AgNPs alone. The combination of Sal and AgNPs had more pronounced effect on cytotoxicity and expression of apoptotic genes and also significantly induced the accumulation of autophagolysosomes, which was associated with mitochondrial dysfunction and loss of cell viability.

Our data show a strong synergistic interaction between Sal and AgNPs in tested cancer cells. The combination treatment increased the therapeutic potential and demonstrated the relevant targeted therapy for the treatment of ovarian cancer. Furthermore, we provide, for the first time, a mode of action for Sal and AgNPs in ovarian cancer cells: enhanced apoptosis and autophagy.

Targeting autophagy using metallic nanoparticles: a promising strategy for cancer treatment https://www.ncbi.nlm.nih.gov/pubmed/30483817

Despite the extensive genetic and phenotypic variations present in the different tumors, they frequently share common metabolic alterations, such as autophagy. Autophagy is a self-degradative process in response to stresses by which damaged macromolecules and organelles are targeted by autophagic vesicles to lysosomes and then eliminated. It is known that autophagy dysfunctions can promote tumorigenesis and cancer development, but, interestingly, its overstimulation by cytotoxic drugs may also induce cell death and chemosensitivity.

For this reason, the possibility to modulate autophagy may represent a valid therapeutic approach to treat different types of cancers and a variety of clinical trials, using autophagy modulators, are currently employed. On the other hand, recent progress in nanotechnology offers plenty of tools to fight cancer with innovative and efficient therapeutic agents by overcoming obstacles usually encountered with traditional drugs. Interestingly, nanomaterials can modulate autophagy and have been exploited as therapeutic agents against cancer.

In this article, we summarize the most recent advances in the application of metallic nanostructures as potent modulators of autophagy process through multiple mechanisms, stressing their therapeutic implications in cancer diseases. For this reason, we believe that autophagy modulation with nanoparticle-based strategies would acquire clinical relevance in the near future, as a complementary therapy for the treatment of cancers and other diseases.

Silver nanoparticles have lethal and sublethal adverse effects on development and longevity by inducing ROS-mediated stress responses https://www.nature.com/articles/s41598-018-20728-z

Silver nanoparticles (AgNPs) are widely used in the household, medical and industrial sectors due to their effective bactericidal activities and unique plasmonic properties. Despite the promising advantages, safety concerns have been raised over the usage of AgNPs because they pose potential hazards. However, the mechanistic basis behind AgNPs toxicity, particularly the sublethal effects at the organismal level, has remained unclear. In this study, we used a powerful in vivo platform Drosophila melanogaster to explore a wide spectrum of adverse effects exerted by dietary AgNPs at the organismal, cellular and molecular levels. Lethal doses of dietary AgNPs caused developmental delays and profound lethality in developing animals and young adults. In contrast, exposure to sublethal doses, while not deadly to developing animals, shortened the adult lifespan and compromised their tolerance to oxidative stress.

Importantly, AgNPs mechanistically resulted in tissue-wide accumulation of reactive oxygen species (ROS) and activated the Nrf2-dependent antioxidant pathway, as demonstrated by an Nrf2 activity reporter in vivo. Finally, dietary AgNPs caused a variety of ROS-mediated stress responses, including apoptosis, DNA damage, and autophagy. Altogether, our study suggests that lethal and sublethal doses of AgNPs, have acute and chronic effects, respectively, on development and longevity by inducing ROS-mediated stress responses

In Vivo Human Time-Exposure Study of Orally Dosed Commercial Silver Nanoparticles https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877176/

In vivo oral exposure to these commercial nanoscale silver particle solutions does not prompt clinically important changes in human metabolic, hematologic, urine, physical findings or imaging morphology. Further study of increasing time exposure and dosing of silver nanoparticulate silver, and observation of additional organ systems is warranted to assert human toxicity thresholds.

In vivo human time-exposure study of orally dosed commercial silver nanoparticles https://www.ncbi.nlm.nih.gov/pubmed/23811290

Human biodistribution, bioprocessing and possible toxicity of nanoscale silver receive increasing health assessment. We prospectively studied commercial 10- and 32-ppm nanoscale silver particle solutions in a single-blind, controlled, cross-over, intent-to-treat, design. Healthy subjects (n=60) underwent metabolic, blood counts, urinalysis, sputum induction, and chest and abdomen magnetic resonance imaging. Silver serum and urine content were determined. No clinically important changes in metabolic, hematologic, or urinalysis measures were identified. Furthermore, no morphological changes were detected in the lungs, heart or abdominal organs. Also, no significant changes were noted in pulmonary reactive oxygen species or pro-inflammatory cytokine generation. In vivo oral exposure to these commercial nanoscale silver particle solutions does not prompt clinically important changes in human metabolic, hematologic, urine, physical findings or imaging morphology. Further study of increasing time exposure and dosing of silver nanoparticulate silver, and observation of additional organ systems are warranted to assert human toxicity thresholds.

Silver: water disinfection and toxicity https://www.who.int/water_sanitation_health/dwq/chemicals/Silver_water_disinfection_toxicity_2014V2.pdf

This literature review, on the use of silver (Ag) as a water disinfectant and the toxicity of silver, is designed as a background document (based on a literature review up to the end of July 2013) for the Expert Working Group on Drinking-water Guidelines and to provide the basis for the development of a short factsheet. The report considers both ionic silver, silver nanoparticles (AgNP) and copper/silver applications.

Local bacteria affect the efficacy of chemotherapeutic drugs https://www.nature.com/articles/srep14554#ref47

In this study, the potential effects of bacteria on the efficacy of frequently used chemotherapies was examined. Bacteria and cancer cell lines were examined in vitro and in vivo for changes in the efficacy of cancer cell killing mediated by chemotherapeutic agents. Of 30 drugs examined in vitro, the efficacy of 10 was found to be significantly inhibited by certain bacteria, while the same bacteria improved the efficacy of six others. HPLC and mass spectrometry analyses of sample drugs (gemcitabine, fludarabine, cladribine, CB1954) demonstrated modification of drug chemical structure. The chemoresistance or increased cytotoxicity observed in vitro with sample drugs (gemcitabine and CB1954) was replicated in in vivo murine subcutaneous tumour models. These findings suggest that bacterial presence in the body due to systemic or local infection may influence tumour responses or off-target toxicity during chemotherapy.

Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine https://www.ncbi.nlm.nih.gov/pubmed/28912244

Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2′,2′-difluorodeoxycytidine) into its inactive form, 2′,2′-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDDL expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.

Illuminating the Anticancerous Efficacy of a New Fungal Chassis for Silver Nanoparticle Synthesis. https://www.ncbi.nlm.nih.gov/pubmed/30800654

Biogenic silver nanoparticles (Ag NPs) have supple platforms designed for biomedical and therapeutic intervention. Utilization of Ag NPs are preferred in the field of biomedicines and material science research because of their antioxidant, antimicrobial, and anticancerous activity along with their eco-friendly, biocompatible, and cost-effective nature. Here we present a novel fungus Piriformospora indica as an excellent source for obtaining facile and reliable Ag NPs with a high degree of consistent morphology. We demonstrated their cytotoxic property, coupled with their intrinsic characteristic that make these biogenic nanoparticles suitable for the anticancerous activity. In vitro cytotoxicity of biologically synthesized Ag NPs (BSNPs) and chemically synthesized Ag NPs (SNPs) was screened on various cancer cell lines, such as Human breast adenocarcinoma (MCF-7), Human cervical carcinoma (HeLa), Human liver hepatocellular carcinoma (HepG2) cell lines and embryonic kidney cell line (HEK-293) as normal cell lines. The antiproliferative outcome revealed that the BSNPs exhibited significant cytotoxic activity against MCF-7 followed by HeLa and HepG2 cell lines as compared to SNPs. The blend of cytotoxic properties, together with green and cost-effective characteristics make up these biogenic nanoparticles for their potential applications in cancer nanomedicine and fabrication coating of ambulatory and non-ambulatory medical devices.

Endoplasmic reticulum stress: major player in size-dependent inhibition of P-glycoprotein by silver nanoparticles in multidrug-resistant breast cancer cells. https://www.ncbi.nlm.nih.gov/pubmed/30670028

Our study suggests that AgNPs are potent inhibitors of Pgp function and are promising agents for sensitizing multidrug resistant breast cancers to anticancer drugs. This potency is determined by their size, since 75 nm AgNPs are more efficient than smaller counterparts. This is a highly relevant finding as it renders AgNPs attractive candidates in rational design of therapeutically useful agents for tumor targeting. In the present study we provide evidence that exploitation of ER stress can be a propitious target in defeating multidrug resistance in cancers.

Silver Nanoparticles: Synthetic Routes, In Vitro Toxicity and Theranostic Applications for Cancer Disease https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977333/

The large use of nanomaterials in many fields of application and commercial products highlights their potential toxicity on living organisms and the environment, despite their physico-chemical properties. Among these, silver nanoparticles (Ag NPs) are involved in biomedical applications such as antibacterial agents, drug delivery vectors and theranostics agents. In this review, we explain the common synthesis routes of Ag NPs using physical, chemical, and biological methods, following their toxicity mechanism in cells. In particular, we analyzed the physiological cellular pathway perturbations in terms of oxidative stress induction, mitochondrial membrane potential alteration, cell death, apoptosis, DNA damage and cytokines secretion after Ag NPs exposure. In addition, their potential anti-cancer activity and theranostic applications are discussed.

Antitumor activity of silver nanoparticles in Dalton’s lymphoma ascites tumor model https://www.ncbi.nlm.nih.gov/pubmed/21042421/

Nanomedicine concerns the use of precision-engineered nanomaterials to develop novel therapeutic and diagnostic modalities for human use. The present study demonstrates the efficacy of biologically synthesized silver nanoparticles (AgNPs) as an antitumor agent using Dalton’s lymphoma ascites (DLA) cell lines in vitro and in vivo. The AgNPs showed dose- dependent cytotoxicity against DLA cells through activation of the caspase 3 enzyme, leading to induction of apoptosis which was further confirmed through resulting nuclear fragmentation. Acute toxicity, ie, convulsions, hyperactivity and chronic toxicity such as increased body weight and abnormal hematologic parameters did not occur. AgNPs significantly increased the survival time in the tumor mouse model by about 50% in comparison with tumor controls. AgNPs also decreased the volume of ascitic fluid in tumor-bearing mice by 65%, thereby returning body weight to normal. Elevated white blood cell and platelet counts in ascitic fluid from the tumor-bearing mice were brought to near-normal range. Histopathologic analysis of ascitic fluid showed a reduction in DLA cell count in tumor-bearing mice treated with AgNPs. These findings confirm the antitumor properties of AgNPs, and suggest that they may be a cost-effective alternative in the treatment of cancer and angiogenesis-related disorders.

Metal-Based Nanoparticles and the Immune System: Activation, Inflammation, and Potential Applications https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466342/

Nanomaterials, including metal-based nanoparticles, are used for various biological and medical applications. However, metals affect immune functions in many animal species including humans. Different physical and chemical properties induce different cellular responses, such as cellular uptake and intracellular biodistribution, leading to the different immune responses. The goals of this review are to summarize and discuss the innate and adaptive immune responses triggered by metal-based nanoparticles in a variety of immune system models.

Silver nanoparticles selectively treat triple‐negative breast cancer cells without affecting non‐malignant breast epithelial cells in vitro and in vivo https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996381/

Silver nanoparticles (AgNPs) show promise for treatment of aggressive cancers including triple‐negative breast cancer (TNBC) in preclinical cancer models. For clinical development of AgNP‐based therapeutics, it will be necessary to clearly define the specific physicochemical features of the nanoparticles that will be used, and to tie these properties to biological outcomes. To fill this knowledge gap, we performed thorough structure/function, mechanistic, safety, and efficacy studies to assess the potential for AgNPs to treat TNBC. We establish that AgNPs, regardless of size, shape, or stabilizing agent, are highly cytotoxic to TNBC cells at doses that are not cytotoxic to non‐malignant breast epithelial cells. In contrast, TNBC cells and non‐malignant breast epithelial cells are similarly sensitive to exposure to silver cation (Ag+), indicating that the nanoparticle formulation is essential for the TNBC‐specific cytotoxicity. Mechanistically, AgNPs are internalized by both TNBC and non‐malignant breast cells, but are rapidly degraded only in TNBC cells. Exposure to AgNPs depletes cellular antioxidants and causes endoplasmic reticulum stress in TNBC cells without causing similar damage in non‐malignant breast epithelial cells. AgNPs also cause extensive DNA damage in 3D TNBC tumor nodules in vitro, but do not disrupt the normal architecture of breast acini in 3D cell culture, nor cause DNA damage or induce apoptosis in these structures. Lastly, we show that systemically administered AgNPs are effective at non‐toxic doses for reducing the growth of TNBC tumor xenografts in mice. This work provides a rationale for development of AgNPs as a safe and specific TNBC treatment.

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