In any case, cancer stem cells are resistant to chemotherapy and radiation 
 therapy.70 The way differentiation therapy works is not by killing cells but by turning 
cancer stem cells into some other cell types that are not cancerous.71
Exposure of DMSO to cancer stem cells could disrupt the cycle of self-renewal 
in cancer stem cells and promote these cells to become a new noncancerous cell type, such as skin cells (Figure 4.2). The reason why this therapeutic approach is 
feasible has to do with some key actions by DMSO on cell cycle activity. Previous 
studies have demonstrated that DMSO can modulate the activator protein-1 (AP-1) activity and lead to cell cycle arrest at the G1 phase. 72 AP-1 is a nuclear transcrip -
tion complex that regulates genetic expression from a variety of stimuli, including 93 DMSO in Genetics
cytokines, growth factors, and stress.73 AP-1 is composed of Jun–Jun and Jun–Fos 
protein dimers that are involved in various biological mechanisms, including normal 
cell growth, differentiation, and tumor development.74
Moreover, an important cell culture finding was recently reported showing DMSO 
as the key stimulator of the tumor suppressor protein called human liver DnaJ-like protein (HLJ1). 75 Tumor suppression was observed when DMSO was able to activate 
AP-1 through JunB and JunD proteins in highly invasive human lung adenocarci -
noma cell line.75 HLJ1 is a novel tumor suppressor protein recently discovered that 
inhibits cancer cell cycle progression, proliferation, invasion, and tumorigenesis and is significantly correlated with relapse and survival and with prognosis in non-small-cell lung carcinoma patients. 76
As a response to DMSO’s tumor-suppressing action, mRNA and protein expres -
sions of HLJ1 were observed to increase in the adenocarcinoma cell lines. Targeted induction of HLJ1 represents a promising approach for cancer therapy. These col -
lective findings imply that DMSO could be a major primary treatment or ligand for the development of anticancer drugs that induce HLJ1
 expression where activation 
of cell migration and cell proliferation pathways can be arrested in cancer cells.75,77
This is an idea that has not yet been experimentally tried and obviously requires 
more basic and clinical exploration. But the reward of finding a nontoxic, active, and cost-effective anticancer agent such as DMSO or its use as an adjuvant to chemo -
therapy or radiation therapy may be an attractive lead to identify a novel therapeutic approach in the search for more effective treatments of invasive cancers. The importance of cancer research and search for effective treatments cannot be 
overstated. Although many new treatments discovered in the last few decades have lowered the incidence of cancer deaths, cancer is still the second most common cause of death in the United States, killing about 600,000 people/year, exceeded only by heart disease. Cancer is estimated by the World Health Organization (WHO) to account for 7.6 million deaths worldwide. Since the collective evidence presented in this chapter indicates that DMSO can 
cause cancer cells to become benign or to arrest their growth, it is important that DMSO research into this important field be stimulated with government or private funding. There are still a number of challenges that need to be addressed in order to trans-
late the research and understanding of cancer stem cells to clinical applications using differentiation-induced therapy as reported for DMSO. These challenges should focus on signaling pathways (which are also shared by normal stem cells), regulation of differentiation, genomics, and proteomics. 75,77
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5DMSO in Basic 
Microbiology
DMSO IN BACTERIAL INFECTIONS
Era of antimicrobials
Microbiology is the study of bacteria, fungi, parasites, and viruses; these are 
 microorganisms that are too small to be seen with the naked eye. Microorganisms 
that are harmful to human health are referred to as pathogens, that is, organisms that 
are capable of causing disease. Most bacteria, however, are not pathogens, and it has been estimated that nonpathogenic or harmless bacteria make up over 70% of all bacteria. It is also estimated that about 100 trillion mostly benign bacteria—called normal flora—are found symbiotically in the human body, primarily in the oral mucosa, intestines, and surface of the skin. Bacterial cells consequently outnumber human cells by a factor of 10 to 1. Normal flora in the body has created the recently discovered human microbiome, an ecosystem that has been linked not only to the digestion of food but also to obesity, depression, asthma, Crohn’s disease, and even cancer. 1
Pathogenic bacteria are the cause of minor and deadly illnesses. Pathogens can 
be broken down into three groups consisting of cocci, bacilli, and spirilla. Cocci are subdivided into three groups, streptococci, diplococci, and staphylococci and are responsible for producing pus and causing boils and pustules. Bacilli notably produce diseases such as influenza and tuberculosis. Spirillum can be the cause of serious disease, including syphilis. Pathogens can spread to infect humans and ani -
mals through a range of vectors including air, water, soil, animals, and insects and by physical contact between the infected host and the noninfected victim. These organisms have wreaked havoc throughout the centuries by decimating a dispropor -
tionately large number of people from such epidemics and pandemics as the plague of Athens in 430 BC, the bubonic (black death) plague in 1338, the great Plague of London in 1665, the cholera pandemic of 1816, and the flu pandemic of 1918, to name but a few. In the history of medicine, probably the greatest breakthrough of all time is the 
start of the antibiotic era and the control of infectious diseases that have been the leading cause of human morbidity and mortality for most of human existence. Prior to the antibiotic era, it was common to believe and easy to record that “the treat -
ment is worse than the disease.” Names like Koch, Pasteur, Domagk, Lister, and Ehrlich were instrumental in changing this cynical cliché by laying the groundwork 
for less toxic and more clinically effective antimicrobial therapy. Their work largely 
paved the way for the chance discovery of penicillin by Alexander Fleming in 1929. 100 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
Fleming made a keen observation noting that the Penicillium notatum  mold acci -
dentally cultured in a petri dish was able to kill several colonies of staphylococci 
bacteria that had also invaded the petri dish near the mold. Despite this monumen -
tal observation, penicillin languished on a laboratory shelf for a decade largely in part because Fleming did not seem to grasp the potential of his great discovery or the conviction to pursue it further. In support of this conclusion, it is well known that Fleming failed to undertake essential experiments where penicillin would be administered to animals infected with pathogens to see whether the animals would be protected and survive the systemic infection. 2 This was and still is a simple rule 
of thumb in experimental pharmacotherapeutics in 1929.
Credit for these animal experiments and penicillin’s clinical effectiveness was 
finally realized in 1939 by a team at Oxford led by Ernst Chain, Howard Florey, who was the head of the laboratory where the work was done, and the chemist Norman Heatley. 3
In 3 years, this team not only showed the bactericidal properties of penicillin in 
animals and humans but also purified, mass-produced, and made penicillin clini -
cally available as an antibacterial agent so that, by 1944, hundreds of thousands of soldiers and civilians were able to survive wound infections sustained in the Second World War that would otherwise may have been fatal. The number of lives saved by penicillin continues to this day. Fleming, Florey, and Chain shared the Nobel Prize in Physiology or Medicine in 1945. The brilliant Spanish physician and scientist Gregorio Marañon referred to peni -
cillin as a miracle cure that opened a new era, full of hope for all humanity. He also prophetically warned that even a miracle cure had its limits. Presently, there are more than a thousand different preparations containing penicillin and over 150 anti -
bacterial agents in the pharmacopoeia to control bacteria, viruses, molds, protozoa, and parasites. At the end of 1945, no one could have predicted that the miracle cure that was 
penicillin would lose some or all of its effectiveness against evolving germs it had easily defeated in the past. The new post-antibiotic era of drug resistance where organisms are able to resist the effects of antibiotics to which they were previously sensitive was now in progress, not only for penicillin but also for many other newer antimicrobials developed after penicillin. Antibiotic-resistant bacteria reveal the amount of sophistication and high adapt -
ability these germs have been able to develop to changing environments. This reaction by disease-producing pathogens poses one of the most serious medical concerns of the twenty-first century because when it is encountered clinically, first-line antibiotic treatments lose their efficacy and second-line antibiotics that may have less efficacy, greater cost, and more safety concerns become the only line of defense. Bacteria that can resist many antibiotics are called multidrug resistant and are commonly referred to as superbugs. These superbugs are especially dangerous in prolonged hospital stays and in intensive care units where an increasing number of invasive measures 
and interventions and inadequate maintenance of hygiene standards pose a high risk 
for infection. 4
Any adjuvant therapy or new approach that potentiates the activity of first-
line antibiotics to prevent antibiotic resistance would help postpone the day when 101 DMSO in Basic Microbiology
antibiotics are no longer generally efficacious.5 This topic and the role played by 
dimethyl sulfoxide (DMSO) as an adjuvant in drug-resistant microbes is discussed in 
the section “How Bacteria Achieve Antibiotic Resistance” in Chapter 6. DMSO AND PATHOGENS
When treating an infection, physicians may face a choice between using a bacteri -
cidal drug, a bacteriostatic drug, and a combination of the two. A bactericidal drug means that it kills bacteria, while a bacteriostatic drug prevents the growth of bac -
teria. The use of one or the other or both is dependent principally on the type of infection being treated and the achievement of a good clinical outcome with the least toxicity. 6
The first observations concerning the bacteriostatic properties of DMSO were 
made by Jacob et al.7 They reported that a 20% solution of DMSO showed bacterio -
static properties against Escherichia coli , Staphylococcus aureus , and Pseudomonas 
bacilli  grown in cultures. Additionally, Jacob’s group also observed that 1% DMSO 
solution altered the sensitivity of resistant tubercle bacilli (the cause of tuberculosis) to antibiotics. As will be seen in Chapter 6, hard-to-cure drug-resistant tuberculosis has become a serious and growing problem worldwide. This occurs when bacteria develop the ability to withstand multiple first-line antibiotic attack and relay that resistant ability to subsequent generations of bacterial offspring. Since that entire strain of resistant bacteria inherits this capacity to fend off the effects of various antibiotics, resistant bacteria can spread from one person to another. Even treatable forms of tuberculosis are particularly tricky to cure because drug-sensitive strains must be treated with a 6-month course of antibiotics. Tougher cases require costly long-term hospitalization and a regimen of multiple drugs that can last years. Patients die when this treatment is ineffective. Perhaps one of the unusual properties of DMSO is its ability to penetrate biologi -
cal membranes or act as a penetrant carrier for other even larger molecules. This property implies that enhancing the penetration of an antibiotic into a bacterial cell, for example, may reduce the concentration needed for the antibiotic to be effective and also reduce its potential toxicity. As a bactericidal agent, DMSO’s minimal inhibitory concentration is reported 
to be 50% for S. aureus  and from 20% to 40% for beta-hemolytic streptococcus, 
Corynebacterium  species, E. coli , and Proteus  species. 8
Pottz et al.9 confirmed Jacob’s team findings and further tested DMSO for bacte -
ricidal and bacteriostatic properties against a variety of microorganisms where they observed growth inhibition at concentrations of 40%–50% (Table 5.1). Pottz et al. 9 found that the bactericidal concentration of DMSO required to inhibit 
the growth of E. coli , A. cloacae , P. vulgaris , beta-hemolytic streptococci group A , 
Salmonella paratyphi B , and C. albicans was 30%, and for P. aeruginosa , it was 
10%. D. pneumoniae  was most sensitive to DMSO and required only  5% concentra -
tion (Table 5.1). S. aureus and Streptococcus faecalis required a 40% and a 50% 
concentration respectively. These microorganisms are responsible for many serious infections, which if left 
untreated can have organ damage consequences or be fatal to the host. For example, 102 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
certain strains of E. coli , which includes serotypes O157:H7, O104:H4 in contami -
nated food or water, can secrete Shiga toxigenic toxins that can result in bloody diar -
rhea and cause severe damage to the lining of the intestines and kidneys.10
A. cloacae  is a rod-shaped bacterium generally found in normal gut flora that 
sometimes causes respiratory and urinary tract infections. Strep throat from beta-
hemolytic streptococci group A is a common throat infection in school-aged children that can lead to a spectrum of more serious diseases including glomerulonephritis and rheumatic fever. 11
S. paratyphi  B and S. faecalis  are contaminants in food and water that often infect 
the intestines and urinary tract. P. aeruginosa  and Candida  species are opportu-
nistic pathogens commonly found in hospital intensive care units where they can cause stubborn infections in patients after surgery. 12 In this list of microbes, the most 
sensitive microorganism to DMSO appeared to be D. pneumoniae  (now known as 
Streptococcus pneumoniae ),9 which is a major cause of pneumonia and a host of 
other infectious diseases such as meningitis, endocarditis, and brain abscesses.13
Shiga toxins from Shigella dysenteriae  or E. coli  inhibit cell-free protein synthe -
sis resulting in multiple cytotoxic effects including neurotoxicity and enterotoxicity. Shiga toxin secreted by Shigella also binds to specific receptors on the cells’ surface in order to attach and enter the cell where it can inactivate the 60S ribosomal subunit to inhibit protein synthesis and cause the destructive lesions seen in shigellosis. DMSO is reported to reduce the endocytosis that occurs after Shiga toxin release and prevent both the cytotoxicity and binding of the Shiga toxin, possibly by its ability to prevent mem -
brane permeability or by inhibiting translocation of the toxin from the cell surface. 14
It was assumed from Pottz et al.’s9 original study that DMSO’s antibacterial action 
may have been through the neutralization of penicillinase, an enzyme produced by some bacteria that provide resistance to beta-lactam antibiotics like penicillin. Further TABLE 5.1
DMSO Bactericidal Activity
Test Microorganism DMSO Minimal Inhibitory Concentration 
0 10 20 40 50
E. coli ++++ ++++ + − −
Aerobacter cloacae ++++ ++++ + − −
Pseudomonas aeruginosa ++++ ++++ ++ − −
Proteus vulgaris ++++ ++++ ++++ − −
S. aureus ** ++++ ++++ ++ − −
Streptococcus pyogenes * ++++ ++++ + − −
Salmonella schottmulleri ++++ ++ ++ − −
Diplococcus pneumoniae ++++ − − − −
Candida albicans ++++ + + − −
Notes:  *, beta-hemolytic streptococcus group A; **, coagulation positive; +, very 
mild growth; ++, mild growth; ++++, strong growth in blood agar or broth 
cultures; −, negative growth.9103 DMSO in Basic Microbiology
experimentation with DMSO to test the possibility that it neutralizes penicillinase’s 
protective action on bacterial growth exposed to penicillin proved negative. Pottz et al.9 
concluded from their extensive findings that the killing action of DMSO on bacteria was not through neutralization of penicillinase. Pottz’s study speculated that, instead, DMSO’s antibacterial action may have been due to dissolution of susceptible micro -
organisms by some unknown mechanism exerted by DMSO. 9 This assumption was 
supported by microscopic analysis of D. pneumoniae smears, which showed that the 
majority of these microbes had dissolved into a sediment after contact with DMSO.9
It is known that the gram-positive microbe S. aureus  can be cleared from murine 
lungs by the bactericidal action exerted by phagocytosis from resident alveolar macrophages without significant contribution from polymorphonuclear leukocytes (PMNs). 15 PMNs’ bactericidal intrapulmonary killing activity is more prominent 
against gram-negative bacteria such as P. aeruginosa . Recent evidence indicates 
that actual phagocytosis of bacteria may not be necessary for intrapulmonary kill of gram-positive microbes and that the majority of inhaled staphylococci in mice are killed without being ingested by resident alveolar macrophages. 16,17
One theory is that reactive oxygen metabolites, including the oxidant superoxide, 
and the radical hydroxyl anion are secreted by phagocytes to create the alveolar bactericidal activity. With this in mind, DMSO was used to test its ability as an antioxidant and hydroxyl radical scavenger to see whether the rate of pulmonary bactericidal activity against P. aeruginosa  and S. aureus  was depressed in infected 
mice. Intratracheal and aerosol delivery of these bacteria were given to mice. 18
DMSO at doses of 50–165 mg/mouse was administered intraperitoneally 30 min 
before challenge with S. aureus  and pseudomonas delivered by either intratracheal 
or aerosol route.18 DMSO was observed to have no activity in inhibiting macrophage 
killing of S. aureus  but did cause a dose-dependent inhibition of pseudomonas clear -
ance from the lungs of treated mice,18 supporting the assumption that alveolar bac -
tericidal action against pseudomonas by PMNs is done through the production of reactive hydroxyl anions that are inhibited by the action of DMSO as a hydroxyl radical scavenger. Conversely, DMSO’s lack of effect in allowing the clearance of S. aureus  from infected murine lung suggests that phagocytic alveolar macrophages 
fail to produce reactive oxygen for bactericidal activity,
19 but this assumption has 
been challenged by others.20
The question arose whether using DMSO clinically for a variety of ailments 
might predispose the user to bacterial infections by inhibiting phagocyte bactericidal activity. This concern grew from an in vitro  experiment where DMSO treatment 
of human and mouse neutrophils and mononuclear phagocytes caused a dose-dependent inhibition of the killing of E. coli  and Listeria monocytogenes . However, 
when the experiment was repeated in vivo  using mice , results showed that adminis -
tration of DMSO prior to subjecting mice to E. coli  and L. monocytogenes  infection 
caused only a slight and nonsignificant decrease in the subsequent in vitro  bacteri -
cidal activity of neutrophils and macrophages from those mice. 21 Repeated injections 
of mice with physiologically relevant doses of DMSO did not increase the lethality of either E. coli or L. monocytogenes , nor did it inhibit the clearance of a sublethal 
Listeria  challenge from the spleen and liver of these mice. The findings indicated that 
clinical usage of DMSO does not predispose human subjects to bacterial infection. 21104 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
Bacterial endotoxin from gram-negative pathogens can directly injure lung endo -
thelial cells in culture. This injury is unaffected by antioxidants such as superoxide 
dismutase or catalase because they are unable to enter cells. Bacterial endotoxins are prevented by DMSO, which penetrates cells to exert antioxidant activity. 22 Since allo -
purinol can inhibit direct lung cell injury from endotoxin, it is probable that xanthine oxidase, which allopurinol is known to inhibit, may be a source of oxidant generation in lung endothelial cells. Current data suggest a two-stage oxidant process of lung cell injury where there is direct injury of the cell both by intracellular generation of toxic oxidants and triggering of an inflammatory response. 22 Inflammatory cells that 
have been activated to adhere to lung cells are able to enhance the injury by generat -
ing and releasing extracellular oxidants, but this process can also be neutralized by DMSO’s anti-inflammatory action. 22
The inability of many antibiotics to enter the blood–brain barrier in mammals 
has been a limiting factor in the treatment of bacterial brain infections such as life-threatening meningitis and brain abcess. 23 Although pathogens can invade the brain 
in a variety of ways, the main pathway is through the bloodstream, where they can enter the subarachnoid space in places where the blood–brain barrier is vulnerable, for example, the choroid plexus. There is some controversy regarding the ability of DMSO to potentiate the penetration of molecules, including antibiotics, across the blood–brain barrier. Previous studies have shown that DMSO enhances the penetra -
tion into the brain of the protein tracer horseradish peroxidase and of ketoconazole, an antifungal agent. 24,25 The ability of DMSO to carry molecules across the blood–
brain barrier may depend on the size of the molecule to be delivered, its polarity, and molecular weight; however, the exact mechanism for achieving such penetration is unknown. 26 It has been suggested that molecules that exceed 70,000 Da (a unit 
of atomic mass) cannot be delivered by DMSO through the blood–brain barrier,25 
suggesting that DMSO may shrink the endothelial cells’ tight junctions that make up the blood–brain barrier to allow small molecules to pass through. This idea was tested on seven healthy adult mares using trimethoprim (TMP)–sulfamethoxazole (SMZ), an effective antimicrobial combination against gram-negative organisms. 27 
A solution of 40% DMSO was injected intravenously at 1 g/kg for 30 min followed immediately after by TMP–SMZ at a combined dosage of 44 mg/kg. The mares were also given the same treatment a week later without DMSO. The combination TMP–SMZ was 543 Da combined, well under the 70,000 Da theoretical limit of DMSO to enhance molecule penetration into the brain. It was found that DMSO was not able to enhance the penetration of TMP–SMZ into the cerebrospinal fluid but did delay the clearance of TMP from serum and increased TMP serum concentration, a finding that had no immediate explanation. 27
These findings add to the unsettled controversy of how and what molecules 
DMSO is able to help penetrate the blood–brain barrier. However, it is clear that penetration of DMSO itself through the intact blood–brain barrier occurs and has been shown to use magnetic resonance spectroscopy. 28
DMSO has been shown to enhance the killing activity of certain bactericidal such 
as peroxynitrite, whereas other hydroxyl radical scavengers cannot. Macrophages and other cells able to produce nitric oxide can generate the formation of peroxyni -
trite, a strong and versatile oxidant and the reaction product of nitric oxide and 105 DMSO in Basic Microbiology
superoxide, which are not strong oxidants themselves.29 Peroxynitrite is highly bac -
tericidal, killing E. coli  in direct proportion to its concentration.30 Three hydroxyl 
radical scavengers mannitol, ethanol, and benzoate did not significantly affect the 
killing potential of peroxynitrite on E. coli  cultures, but 100 mM DMSO did enhance 
peroxynitrite-mediated killing. DMSO is a more efficient hydroxyl radical scavenger than the other three scavengers and increases the formation of nitrogen dioxide to enhance the killing power of peroxynitrite. 30
Helicobacter pylori  is a spiral, intragastric bacterium that can be found in at least 
a third to half of people worldwide, most of whom have no symptoms. The frequency of H. pylori  infection varies from country to country with 70%–90% of adults har -
boring the microbe in underdeveloped countries to about 50% in the United States found carrying the bacterium in 60-year-olds. 31
H. pylori  can help the human body by helping to regulate the level of stomach acid 
secreted, and as it does, it creates a beneficial environment both for itself and its host. When this regulation of acid secretion is disturbed, a series of molecular changes in the stomach can occur where H. pylori  strains become harmful to its host. When that happens, the dark side of H. pylori  is revealed as the causative organ -
ism in peptic ulcer disease and chronic gastritis. The H. pylori  pathogenic strain is 
also linked to the development of duodenal ulcers and distal stomach adenocarci -
noma. The discovery of H. pylori  as the cause of peptic ulcer disease came about 
after Freedberg and Baron
32 found in 1940 spirochetes in about 40% of gastric biop -
sies. Even thought there were sporadic reports occasionally appearing in the medical literature about the association of H. pylori  and peptic ulcers, the great majority of 
gastroenterologists believed that these ulcers arose principally from lifestyle factors or from physical and emotional stress due to acid secretion. The fact that H. pylori  
was capable of living in the acidic environment of the stomach was a major reason for most gastroenterologists to dismiss its potential pathogenicity because no one could envision how a bacterium could survive for long in such an environment. Until 1984, anyone training in medicine was taught the axiomatic golden rule, 
“no acid, no ulcer,” the intention being that peptic ulcers can occur only when the stomach secretes acid. 33 This long-standing and erroneous principle supported by no 
solid evidence of any kind became an unchallenged medical dictum in the teaching and management of gastric ulcers. The “no acid, no ulcer” rule also led to a finan-cial boom for many pharmaceuticals that manufactured a hodgepodge of antacids. However, in 1983, a year before the continued pursuit of antacids for the treatment of ulcer disease, two Australian physicians, Robin Warren and Barry Marshall,
34 boldly 
and correctly identified and later successfully treated peptic and duodenal ulcers with antibiotics despite violent opposition by the medical establishment at the time. Their work not only cured a serious gastroduodenal disorder that afflicted millions of 
patients worldwide but also prevented a highly lethal cancer of the  s tomach. Marshall 
and Warren shared the Nobel Prize in 2005. The Warren–Marshall  d iscovery has 
generated over 50,000 scientific publications to this date and has resulted in a signifi -
cant decline of gastroduodenal ulcers in most Western countries.35
H. pylori is presently treated with a triple therapy consisting of two antibiotics, 
clarithromycin and amoxicillin, and a proton-pump inhibitor omeprazole.36 This 
regimen has considerable side effects. Moreover, the increase in antibiotic resistance 106 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
by this bacterium has led to the search for new therapeutic strategies, including anti-
inflammatory agents and hydroxyl radical scavengers. Searching for other options to treat H. pylori , an in vitro  study removed H. pylori  
strains  isolated from antral biopsy specimens and cultured these pathogens on sheep 
blood agar.37 An agar diffusion test was used to screen the antibacterial effect of 10% 
DMSO and 1% allopurinol. It was found that therapeutically administered concen -
trations of DMSO and allopurinol had no growth-inhibiting effect on H. pylori in 
vitro.37 No zones of inhibition were produced by either drug.37 This study concluded 
that neither DMSO nor allopurinol at the doses used is suitable for H. pylori eradica -
tion treatment. A cautionary note was added to these negative findings by pointing out the limits of in vitro  testing since it could not be ruled out that DMSO may work 
to interfere with adherence factors of H. pylori and, in this way, block this microbe 
from recolonization of the gastroduodenal epithelium and prevent duodenal ulcer relapse. 37
The role of oxyradicals in the process of acute and chronic duodenal ulceration 
in the rat was examined by administering allopurinol and DMSO by gavage. To produce chronic duodenal ulceration, all rats received intramuscular reserpine injec -
tions (0.1 mg/kg) every day for 6 weeks. Pretreatment was given with dose-dependent DMSO and allopurinol. At least 70% of rats were protected against ulceration with 5% or 10% solutions of DMSO, and similar concentrations of allopurinol protected 
all  a nimals. Neither agent was seen to protect rats from influencing the hyperchlor -
hydria.38 These findings appeared to indicate that oxygen-derived free radicals 
played an important role in the formation and development of gastric ulcers and led to translationally examine DMSO and allopurinol in a clinical setting in patients diagnosed with H. pylori . 38
In a randomized, controlled clinical study on 146 patients, cimetidine, placebo, 
and the free radical scavengers allopurinol and DMSO were tested to see their effects on H. pylori  duodenal ulcer relapse, which is believed to be mediated by oxygen-
derived free radicals. 38 DMSO was given orally at doses of 500 mg four times daily, 
allopurinol at 50 mg four times a day, and cimetidine 400 mg at bedtime to patients who had shown endoscopic healing from gastric mucosal infection with H. pylori . 38 
Treatment of these agents continued for 1 year. During the follow-up endoscopy at 6 and 12 months, the cumulative relapse at 1 year was placebo 47%, cimetidine 24%, allopurinol 6%, and DMSO 6%. In the patients who relapsed, ulcer recurrence tended to occur early in those patients taking a placebo or cimetidine, while ulcer relapse tended to be evenly distributed over the year for the patients treated with DMSO or allopurinol. The conclusions from this study suggest that oxygen-derived free radicals are involved in the relapse of duodenal ulceration in patients infected with H. pylori . 38
P. aeruginosa  is a common opportunistic pathogen of humans, animals, and 
plants. This bacterium can colonize the respiratory tract in hospital-acquired infec -
tions particularly in immunocompromised or mechanically ventilated people.39
Because it thrives on most surfaces, this P. aeruginosa  can colonize medical 
equipment, including in-dwelling catheters, causing cross-infections in hospitals and clinics. It has been shown that several P. aeruginosa  virulence factors, both 
cell-associated and extracellular products, are potent inducers of proinflammatory 107 DMSO in Basic Microbiology
mediators, such as the interleukins, a large group of cytokines mainly produced 
by PMNs and leukocytes during inflammation. In particular, interleukin-8 (IL-8) overexpression has been shown to induce ulcer formation in the cornea through neu -
trophil recruitment. 40 Interleukin-8 is often associated with inflammation. IL-8, also 
known as neutrophil chemotactic factor , has two primary functions. It induces che -
motaxis in target cells, primarily neutrophils but also other granulocytes, causing them to migrate toward the site of infection, and also induces phagocytosis once they have arrived. 41 Chemotaxis is a process whereby bacteria and other cells move 
toward an object according to certain chemicals in their environment. This is fun -
damentally important for bacteria to move forward to find food or move away from a noxious source. A relationship has been found between massive accumulation of neutro -
phils, mainly due to enhanced IL-8 levels, to contribute to lung infections from P. aeruginosa . 42
The role of DMSO as an anti-inflammatory and free radical scavenger43 was inves -
tigated in the possible inhibition of IL-8-mediated neutrophil recruitment induced by P. aeruginosa  bacterial supernatant. 44 The test involved the question of IL-8 inhi -
bition in vitro induced by P. aeruginosa  in human bronchial epithelial cells. These 
cells produce IL-8 induced by P. aeruginosa , a process that was blocked by 1% 
exposure to DMSO as measured by the concentrations of RNA and protein  p resent. These findings were extended to examine whether DMSO prevented the recruitment of neutrophils and IL-8 production induced by P. aeruginosa
 in dog  t rachea. It was 
seen that DMSO was able to prevent IL-8 production in the dog airway epithelial cells induced by P. aeruginosa . The mechanism for this inhibitory action by DMSO 
is not known but may be due to its anti-inflammatory effects and hydroxyl radical scavenger activity of recruited neutrophils since it has been shown that airway epi -
thelial cells can form oxygen radicals and hydroxyl radicals after exposure to inflam -
matory mediators such as IL-8. 44
Aside from their effects on airway epithelial cells, production of reactive oxygen 
species from bacterial toxins also contributes to the pathophysiology of intestinal inflammation. This is the case of the enterotoxic effects of toxin A generated by Clostridium difficile . C. difficile  is a slow-growing, spore-forming anaerobe that is found in the normal 
gut flora in 80% of healthy neonates and in the majority of people. 45 C. difficile  can 
remain in check in the gastrointestinal tract normal flora until its destructive power is unleashed following antibiotic treatment that can eradicate other competing bac -
teria from the intestine, disrupt the normal microbiome, and result in colitis and diarrhea. 46
Following antibiotic treatment and proliferation by C. difficile , two potent entero -
toxins designated A and B are released by C. difficile , causing an acute inflammatory 
reaction and damage to the mucosal cells of the lamina propria in the large bowel.46 
These toxins are responsible for the enterocolitis and diarrhea that results from C. 
difficile  infection.46 After their release, toxin A or B or both can enter the cytosol 
of target cells where pseudomembranous colitis develops, characterized by loss of appetite, fatigue, offensive-smelling diarrhea, fever, and abdominal pain. In severe cases, life-threatening complications can develop, such as toxic megacolon.108 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
C. difficile  infection of the bowel in adults can be treated with oral vancomycin or 
preferably, with oral metronidazole, 500 mg three times/day for 2 weeks.47 However, 
both medications have side effects, and in particular, metronidazole can cause addi -
tional pseudomembranous colitis, hives, and swelling of the face, lips, and throat.48 
Pediatric C. difficile  infection appears to be on the rise, and some cases can be life-
threatening.49 The search for more effective and safer treatments for C. difficile has 
therefore become a medical priority.50
Infection with C. difficile  also poses a socioeconomic problem for health-care 
costs. The estimated number of cases of C. difficile –associated disease exceeds 
250,000 per year in the United States alone with total additional health-care costs 
approaching 1 billion dollars annually.51
The search for alternative therapy to C. difficile  led Qiu et al.52 to test the action 
of DMSO on reactive oxygen metabolites, which have been implicated in the patho -
genesis of experimental colitis in both animal models and idiopathic inflammatory bowel disease of humans. 53 Reactive oxygen metabolites are mainly free radicals that 
appear to mediate damage to proteins and lipids in tissues targeted by C. difficile .52 
These free radicals include superoxide, hydroxyl ion, and hypochlorite, which may be involved in toxin A production generated by C. difficle . 52 Rats were subjected to a 
laparotomy, and two closed ileal loops were formed in each anima. Five microliters of toxin A was administered by intraluminal injection to each animal. Seven days prior to toxin A administration, rats were treated with 0.1%–5% DMSO or control buffer. Results of DMSO treatment are summarized in Figure 5.1. Results of DMSO treatment and partial inhibition of toxin A support the 
assumption that hydroxyl and superoxide radicals contribute to the effects of toxin A–induced acute enteritis inflammation and microvascular injury to the rat ileum. 52 
The finding that only partial inhibition of toxin A by DMSO was seen (Figure 5.1) suggests that other mediators such as prostaglandins and leukotrienes may also play a role in toxin A damage. 54
These findings could be useful in the treatment of ulcerative colitis and Crohn’s 
disease in humans since they are also characterized by reduced levels of antioxidant molecules that can neutralize inflammation generated by activated neutrophils and monocytes. Data to support this assumption have been reported showing oxidant damage in the inflamed mucosa of Crohn’s patients but not in patients with prior Crohn’s disease who had healing of the colon mucosa. 53
DMSO IN VIRAL AND FUNGAL PATHOLOGY
One of the first antiviral uses of DMSO was a formulation for the treatment of oral herpes simplex in humans. Herpes simplex is an infection caused by a herpes sim -
plex virus (HSV), which enters the body and forms blisters, itch, and pain and then heals and disappears. There are two types of herpes viruses: HSV-1 and HSV-2. Both types can cause lesions in the mouth and genitals, but HSV-1 is more predomi -
nant in cold sores of the mouth. Genital herpes affects the genitals, buttocks, or anal area. 55 Genital herpes is a sexually transmitted disease. Other herpes infections can 
affect the eyes, skin, or other parts of the body. Once an infection occurs, the virus 109 DMSO in Basic Microbiology
spreads to nerve cells and stays in the body for the rest of a person’s life. It may come 
back from time to time and cause symptoms or flares. Many antiviral preparations have been introduced to alleviate the pain and heal -
ing of oral herpes, some better than others, including DMSO.56,57
One of the better antiviral preparations for herpes is a formulation consisting of a 
5% solution of idoxuridine in various concentrations combined with DMSO. A small amount of the idoxuridine–DMSO solution was painted on the herpetic lesions of 16  patients, and details of the progress of the lesions were recorded daily by an observer in a double-blind manner. 58
The duration of the attack until the arrest of lesion was 1.2 days in the group 
receiving idoxuridine–DMSO and 2.45 in those receiving only DMSO. Thus, there seemed to be a synergistic action when using idoxuridine–DMSO solution as opposed 
to DMSO alone. Both drugs were more effective than no treatment. 58 This study 
has been replicated many times following results from a study by Spruance et al.,59 
which showed significant acceleration of healing in herpes labialis lesions when 
Toxin A + DMSO treatmen t
**
**
****
*
*
**
****500
(a)400
300
200
100
0
40000[3H] Mannitol (dpm/cm) loop/4 h Loop weig ht/leng th (mg/cm/4 h)
20000
0
(b)Buﬀer Toxin A 0.1% 0.5% 1% 5%
FIGURE 5.1  Inhibition of toxin A by dose-dependent DMSO treatment given orally 7 days 
before toxin exposure in rat-induced colitis. DMSO effective response is seen in concentra -
tions between 0.1% and 5%. Key: Results are expressed as means ± SE of 8 loops/group. (a) 
Fluid-induced secretion of toxin A. (b) Mucosal permeability to mannitol. *p ≤ 0.05 DMSO 
versus buffer control; **p ≤ 0.01 DMSO versus toxin A alone. (Adapted from Qiu, B. et al., 
Am. J. Physiol ., 276(2 Pt 1), G485, 1999. )110 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
301 immunocompetent patients were treated with a solution of 15% idoxuridine–80% 
DMSO solution. Idoxuridine–DMSO preparation has been approved for herpes 
 zoster in Canada and Europe.60
Another antiviral agent tested for the treatment of herpes simplex infection is 
topically administered acyclovir in polyethylene glycol (Acy-PEG). A comparison of this Acy-PEG ointment preparation was made versus acyclovir–DMSO ointment in excised human and guinea pig skin. 61 Results from this study established that Acy-
PEG formulation penetrates human skin very slowly.61 This result was attributed to 
PEG inefficacy since the preparation using acyclovir–DMSO ointment was signifi -
cantly more effective. A more consistent interpretation of this study is that DMSO appears to exert antiviral activity by itself since it was found that acyclovir ointment alone had only limited therapeutic benefit. 61 There is, in fact, corroboration for this 
latter conclusion from another independent study done in Spain. That study reports that although DMSO has been regarded as a useful excipient 
that can carry active antiviral agents across membranes to increase penetration into tissues of these agents, findings show that DMSO may express antiviral activity by itself. 62 Rabbit skin fibroblasts were used to grow the recombinant HSV-1 and Vero 
cells to analyze the action of DMSO.62 DMSO was able to block productive infection 
in HSV-1 in Vero cells when administered after virus adsorption. DMSO appears to cause this block in HSV-1 production by acting at different sites with positive cooperativity, as suggested by the Hill numbers of the inhibition curves. 62 The results 
indicated that DMSO inhibits HSV-1 viral DNA synthesis in vitro , blocked the sta -
bility and maturation of the free virion, and also reduced the levels of a number of viral transcripts. 62 Thus, it was concluded from this study that DMSO may possess 
antiviral activity by previously undisclosed inhibitory mechanisms. This important finding should be considered in relation to how herpes infec -
tions can progress to serious disorders. Although most of herpes infections are mild, they can lead to lethal encephalitis, and this virus accounts for 20% of all reported encephalitis cases. 63
To our knowledge, there are no studies that have used DMSO either as an adju -
vant or as a primary therapy in human viral encephalitis. Paradoxically, DMSO with acyclovir has been used for the prophylaxis and therapy of equine herpes virus type 1 (EHV-1) infection, which can cause myeloencephalopathy and death in horses. 64,65
Since DMSO has been used as a solubilizing and penetrant carrier for other antivi -
ral agents for such conditions as rabies and viral-induced myocarditis,66,67 it is logical 
and justified to reappraise the potential antiviral activity by DMSO in the interest of drug safety since many of the antiviral agents on the market have adverse effects that could be avoided by considerably lowering their dose when combined with DMSO. DMSO is a frequently used solvent and penetrant carrier through the skin for 
antifungal drugs. DMSO is recommended to dissolve antifungals with poor aque -
ous solubility, but recently, DMSO has gained attention for drugs that are currently prepared in water. Using DMSO to prepare all approved antifungals would increase the consistency 
of the methods for drug preparation listed in the current Clinical and Laboratory Standards Institute guidelines and could help avoid precipitation of the antifungal agents, which would impair their efficacy. 68111 DMSO in Basic Microbiology
DMSO by itself has shown effectiveness against the strains of many fungi that 
cause skin, hair, and nail infections, including trichophyton, epidermophyton, and 
microsporum at dose-dependent concentrations of 1%–10%.69 Trichophyton is a skin 
infection that causes athlete’s foot, ringworm, jock itch, and similar dermatophyte infections of the nail, beard, skin, and scalp, while epidermophyton and microspo -
rum affect hair, skin, and nails. 70
DMSO was evaluated in vitro  at a 2% concentration against an assortment 
of Candida species and was observed to slow the growth of all Candida isolates tested. 71
Antifungal activity by DMSO was also observed recently at concentrations 
between 0.5% and 1% against six yeast species, including Candida  species.72
The antifungal effects of DMSO are especially important in the geriatric popu -
lation due to the higher prevalence of seborrheic dermatitis, mucosal and cutane -
ous candidiasis, tinea pedis, and onychomycosis found in this group of patients.73 
Treatment of these elderly people with dermatophytoses and yeast infections should depend on the patient’s medication list to avoid potential drug interactions and whether topical or systemic therapy is indicated. 73
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moter. J Biol Chem. 2009;284(7):4191–4199. 40. Xue LM, Willcox MD, Lloyd A, Wakefield D, Thakur A. Regulatory role of IL-1 β in 
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Dimethyl_Sulfoxide_(DMSO)_in_Trauma_and_Disease_[2015].txt
Summarize the following text section accurately and concisely. Maintain specific details and numerical information, and use anti-repetition mechanisms:

        In any case, cancer stem cells are resistant to chemotherapy and radiation 
 therapy. 70 The way differentiation therapy works is not by killing cells but by turning 
cancer stem cells into some other cell types that are not cancerous. 71
Exposure of DMSO to cancer stem cells could disrupt the cycle of self-renewal 
in cancer stem cells and promote these cells to become a new noncancerous cell type, such as skin cells (Figure 4. 2). The reason why this therapeutic approach is 
feasible has to do with some key actions by DMSO on cell cycle activity. Previous 
studies have demonstrated that DMSO can modulate the activator protein-1 (AP-1) activity and lead to cell cycle arrest at the G1 phase. 72 AP-1 is a nuclear transcrip -
tion complex that regulates genetic expression from a variety of stimuli, including 93 DMSO in Genetics
cytokines, growth factors, and stress. 73 AP-1 is composed of Jun–Jun and Jun–Fos 
protein dimers that are involved in various biological mechanisms, including normal 
cell growth, differentiation, and tumor development. 74
Moreover, an important cell culture finding was recently reported showing DMSO 
as the key stimulator of the tumor suppressor protein called human liver DnaJ-like protein (HLJ1). 75 Tumor suppression was observed when DMSO was able to activate 
AP-1 through JunB and JunD proteins in highly invasive human lung adenocarci -
noma cell line. 75 HLJ1 is a novel tumor suppressor protein recently discovered that 
inhibits cancer cell cycle progression, proliferation, invasion, and tumorigenesis and is significantly correlated with relapse and survival and with prognosis in non-small-cell lung carcinoma patients. 76
As a response to DMSO’s tumor-suppressing action, mRNA and protein expres -
sions of HLJ1 were observed to increase in the adenocarcinoma cell lines. Targeted induction of HLJ1 represents a promising approach for cancer therapy. These col -
lective findings imply that DMSO could be a major primary treatment or ligand for the development of anticancer drugs that induce HLJ1
 expression where activation 
of cell migration and cell proliferation pathways can be arrested in cancer cells. 75,77
This is an idea that has not yet been experimentally tried and obviously requires 
more basic and clinical exploration. But the reward of finding a nontoxic, active, and cost-effective anticancer agent such as DMSO or its use as an adjuvant to chemo -
therapy or radiation therapy may be an attractive lead to identify a novel therapeutic approach in the search for more effective treatments of invasive cancers. The importance of cancer research and search for effective treatments cannot be 
overstated. Although many new treatments discovered in the last few decades have lowered the incidence of cancer deaths, cancer is still the second most common cause of death in the United States, killing about 600,000 people/year, exceeded only by heart disease. Cancer is estimated by the World Health Organization (WHO) to account for 7. 6 million deaths worldwide. Since the collective evidence presented in this chapter indicates that DMSO can 
cause cancer cells to become benign or to arrest their growth, it is important that DMSO research into this important field be stimulated with government or private funding. There are still a number of challenges that need to be addressed in order to trans-
late the research and understanding of cancer stem cells to clinical applications using differentiation-induced therapy as reported for DMSO. These challenges should focus on signaling pathways (which are also shared by normal stem cells), regulation of differentiation, genomics, and proteomics. 75,77
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Cancer stem cells are resistant to chemotherapy and radiation therapy.
What is the primary mechanism of action of chemotherapy and radiation therapy?
Differentiation therapy works by turning cancer stem cells into non-cancerous cell types.
What is the purpose of differentiation therapy?
The text does not explicitly state the role of DMSO in the treatment of cancer, but it does discuss its potential to induce the differentiation of cancer stem cells into non-cancerous cell types.
What is the role of DMSO in the treatment of cancer?
The text does not explicitly state the significance of DMSO in the treatment of bacterial infections, but it does discuss its potential antiviral and antibacterial properties.
What is the significance of DMSO in the treatment of bacterial infections?
The study aimed to investigate the effect of DMSO on the expression of IL-8 in human corneal epithelial cells during Pseudomonas aeruginosa colonization.
What is the purpose of the study on the inhibition of IL-8 expression in human corneal epithelial cells?