The discovery that imiquimod may act through an immune-independent mechanism opens new possibilities for the use of this compound and its analogs in the treatment of cancers and many other diseases.
In a recent publication in the August issue of the journal Experimental Biology and Medicine, researchers from Pennsylvania State University College of Medicine (PA, USA) have demonstrated a new pathway in which imiquimod works, opening new possibilities for therapeutic use of this compound in cancers and many other diseases.
Imiquimod (C14H16N4; Aldara™) is effective in the treatment of external genital and anal warts, basal cell carcinoma, actinic keratoses, Kaposi’s sarcoma, chronic hepatitis C infection and intraepithelial carcinoma. The drug belongs to the imidazoquinoline class that also includes resiquimod and is reported to act as a Toll-like receptor (TLR)7 agonist. Hence, the anticancer effect of imiquimod is thought to be through immunomodification involving various cytokines, which leads to apoptosis.
The research team led by Ian Zagon has used tissue cultures of cancer cells (pancreatic, colorectal and squamous carcinoma cells of the head-and-neck cancers) to show that imiquimod could upregulate the opioid growth factor (OGF) receptor, ‘which in turn stimulates the interaction of the OGF–OGF receptor axis. This native, tonically active inhibitory pathway regulates cell proliferation by modulating cyclin-dependent kinase inhibitors, resulting in a retardation of cells at the G(1)–S interface of the cell cycle. Neutralization of OGF or knockdown of OGF receptor by siRNA technology eliminates the inhibitory effects of imidazoquinolines on cell replication’, wrote the authors.
“Our data brings a paradigm shift to our thinking about a drug widely used in the clinics. Rather than imiquimod activity being mediated by induction of various cytokines, including IFN-α, IFN-γ, TNF-α, IL-1α and IL-12, as currently thought, an entirely new pathway – native to body chemistry – has been discovered to regulate cell proliferation by imidazoquinolines,” said Zagon.
“The elucidation of imiquimod’s immune-independent mechanism of action in cancer also creates exciting new therapeutic possibilities for a number of noncancer conditions, and these are now being further explored. Such studies could lead to new off-label applications for imiquimod as well as development of imiquimod analogs and unique combination therapies,” added coauthor Moshe Rogosnitzky.
Source: Zagon IS, Donahue RN, Rogosnitzky M, Mclaughlin PJ. Imiquimod upregulates the opioid growth factor receptor to inhibit cell proliferation independent of immune function. Exp. Biol. Med. 233, 968–979 (2008).
Potential approach to enhance T-cell production
Researchers from the University of Montreal (Canada) and University of Oulu (Finland) have discovered a new function of the Wingless-related protein (Wnt)4 in stimulating the production of T cells in the thymus. Results were published in the July issue of the journal Immunity.
Age-related atrophy of the thymus leads to a decrease in the number of T cells that mature in the thymus, as well as their ability in recognizing antigens. This often happens in people 50 years of age and older, resulting in a weakened immune system and exposing these people to infections and tumor development.
“Thymic atrophy is a major public health problem,” said Claude Perreault of the University of Montreal, the lead author of the study. “It compromises the efficacy of vaccination and weakens the resistance to common viruses, for instance to the respiratory syncytial virus, which is responsible each year for the hospitalization of more than 150,000 people in the USA. This is due to the fact that ‘old’ T cells are not equipped to face the threat of new foreign bodies, whether they are viruses or tumors.”
Overexpression of the Wnt4 protein in mouse immune cells increased number of white blood cell progenitors and, vice versa, deletion of the Wnt4 gene (hence no protein expression) led to a decrease in the number of T-cell progenitors in the thymus. The research team was also able to show ‘that Wnt4 activates noncanonical (β-catenin-independent) signaling and that its effects on hematopoietic cells are mainly non-cell-autonomous’. The new function of the Wnt4 protein might be harnessed in new therapeutic approaches to tackle age-related atrophy of the immune system.
Sources: Louis I, Heinonen KM, Chagraoui J, Vainio S, Sauvageau G, Perreault C. The signaling protein Wnt4 enhances thymopoiesis and expands multipotent hematopoietic progenitors through β-catenin-independent signaling. Immunity 29(1), 57–67 (2008); Université de Montréal, Canada www.umontreal.ca
Project to boost parents’ confidence with MMR vaccination
As measles cases are on the rise with many unvaccinated children in the UK, it is necessary to keep parents fully informed when they make decisions on whether to vaccinate their children.
With the recent rise in measles cases in the UK, a new project has been set up to raise parents’ confidence in vaccination. Parents should be better informed regarding the risk of measles, mumps and rubella (MMR) that their child may get, and encouraged to immunize their child with the MMR vaccine.
According to the UK Health Protection Agency, cases of measles reached a new peak in London last May, and a teenage boy in West Yorkshire became the first person to die from the disease in the last 2 years in the UK. In 2007, a record of 971 measles cases were reported, a 30% increase compared with 2006.
Despite the availability of the MMR vaccine, there are several hundred thousand unvaccinated children in the UK. This is mainly because parents have not been given enough information when making their decision, and they do not feel confident following controversy regarding the safety of the MMR vaccine. “We are extremely concerned that the incidence of measles has risen to high levels because MMR vaccination rates have fallen,” said Simon Balmer, Head of Health Protection for the Leeds Primary Care Trust, UK.
“Mumps, measles and rubella are all serious diseases and become more so the older you get. If an unvaccinated pregnant woman gets rubella, then a damaged child may be the future price the family will pay for getting this wrong now. Health professionals need to have credible and appropriate information to give to those parents about to make a decision about immunizing their children,” said Martin Schweiger, consultant in communicable disease control at the West Yorkshire Health Protection Unit.
In this new project, health experts from Leeds University (UK) and the University of Sydney (Australia) aim to provide parents with sufficient information that may answer their concerns and assist their decision making, using a new software developed at the University of Sydney.
“Parents criticize the literature and information currently available. They don’t feel confident about saying yes to the vaccine when they don’t know enough,” said Cath Jackson, a team member. “We will be testing the Australian software alongside more traditional materials to find out the best way of giving parents the right support and information they need to make a decision about MMR.”
“Our previous research shows that many parents were unconvinced that the MMR vaccine is safe and 62% did not consider that their MMR decision was informed. However, there was little opportunity to talk about reaching a decision because GPs and nurses simply don’t have the time. We found that some parents feel pressured into making an instant decision about MMR with health professionals assuming they will vaccinate their children,” explained Jackson.
The new project is funded by the UK National Institute for Health Research. Hundreds of new parents will be recruited and assisted in making their first decision about vaccination. “With the right information, we believe that most parents will choose to vaccinate their children against these serious illnesses,” commented Balmer.
Source: University of Leeds, UK www.leeds.ac.uk
New priorities set by the NIAID for HIV vaccine research
HIV vaccine research has been reshaped by the National Institute of Allergy and Infectious Diseases (NIAID), part of the US NIH. Two new initiatives, Basic Vaccine Discovery and Highly Innovative Tactics to Interrupt Transmission of HIV have been created, which will provide funding to individual investigators for basic vaccine research and novel approaches to interrupt HIV transmission.
In addition, the NIAID also works closely with other organizations at the NIH to better assist nonhuman primate (NHP) research, which is key to HIV vaccine design and evaluation. A new workshop will be organized in November 2008 to identify needs and directions of NHP researchers. Young investigators in the HIV vaccine field will be encouraged and supported in obtaining their first grants. Scientist exchange between basic research and human clinical trials will be promoted within the NIAID’s HIV Vaccine Trials Network (HVTN) to strengthen the bridge between NHP and human research and enable more direct comparisons of results.
The NIAID plans to reconsider the number of awards given to preclinical HIV vaccine development, while ensuring its HVTN structure is flexible to accommodate the number and size of human clinical trials.
Sources: Fauci AS, Johnston MI, Dieffenbach CWet al.HIV vaccine research: the way forward. Science 321(5888), 530–532 (2008); National Institute of Allergy and Infectious Diseases www.niaid.nih.gov
Intravenous vitamin C might help fight cancers
New research in mice has renewed interest in the use of high-dose vitamin C in cancer treatment.
Intravenous injection of vitamin C at a high dose could reduce tumor growth and size, as well as prevent their spread in mouse models of brain, ovarian and pancreatic cancers. The findings were published in the August issue of the Proceedings of the National Academy of Sciences.
Vitamin C (ascorbate or ascorbic acid) is vital in many enzymatic functions and is known to have antioxidant property in which it protects cells from free radicals. Its concentration is tightly regulated. “When you eat foods containing more than 200 mg of vitamin C a day – for example, two oranges and a serving of broccoli – your body prevents blood levels of ascorbate from exceeding a narrow range,” said Mark Levine, the study’s lead author and chief of the Molecular and Clinical Nutrition Section of the National Institute of Diabetes and Digestive and Kidney Diseases, part of the US NIH.
Previous studies have suggested the potential anticancer effect of high-dose vitamin C. However, in two double-blind, placebo-controlled clinical trials in 1979 and 1985, no benefit was observed in cancer patients taking high oral doses of vitamin C. “Clinical and pharmacokinetic studies conducted in the past 12 years showed that oral ascorbate levels in plasma and tissue are tightly controlled. In the case series [prior to these two clinical trials], ascorbate was given orally and intravenously, but in the trials ascorbate was just given orally. It was not realized at the time that only injected ascorbate might deliver the concentrations needed to see an anti-tumor effect,” explained Levine.
The NIH researchers have injected high doses (up to 4 g/kg bodyweight) of vitamin C into the abdominal veins of immune-deficient mice with ovarian, pancreatic and glioblastoma (brain) tumors. “At these high injected doses, we hoped to see drug-like activity that might be useful in cancer treatment,” said Levine.
Injected animals showed reduced tumor growth and size by 41–53%. No tumor spreading was observed in treated glioblastoma mice, while 30% of untreated mice showed tumor spreading to other organs. In vitro experiments also showed the anticancer effect of high-dose vitamin C in 75% of the 42 cancer cell lines, while the treatment did not affect normal cells.
The authors suggested that the anticancer effect of vitamin C might be due to the formation of hydrogen peroxide in the extracellular fluid surrounding the tumors; in other words, high-dose vitamin C has a pro-oxidant effect (i.e., producing free radicals that kill cancer cells but not normal cells). “These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options,” the authors concluded.
Sources: Chen Q, Espey MG, Sun AY et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl Acad. Sci. USA. 105(32), 11105–11109 (2008); National Institute of Diabetes and Digestive and Kidney Diseases, MD, USA www.niddk.nih.gov