Chloroquine and Cancer Treatment !

Strange as it may sound, but it is true. Yes, this is what a group of researchers from Harvard Medical School recently reported in a reputed journal.  I believe most of us especially those living in India and Africa, are well aware of Chloroquine, which is known as one of the most widely and successfully used first generation anti-malarial drug.  It is very famous (for its effectiveness) rather infamous (for its characteristic bitter taste), I still remember during my childhood back in India, elders used to threaten kids that if they won’t sleep in bed equipped with mosquito nets, they would have to eat chloroquine, and all kids out of fear for chloroquine rather malaria itself, would immediately agree to go to bed under the net (which they otherwise did not like normally). Anyways, in last few decades because of emerging chloroquine-resistant malaria parasites, chloroquine was almost forgotten and researchers started to look for other more effective and less toxic drugs to treat and prevent malaria. It is only last couple of years that chloroquine got sudden attention especially among biologists when cancer biologists noticed its role as an inhibitor of autophagy.

Autophagy (from Greek auto-oneself, phagy-to eat) is a process of self-cannibalization which is dependent on the presence of autophagosomes, autolysosomes, as well as an intact nucleus in the cell. Autophagy was first described in the 1960s but many questions about the actual processes and mechanisms involved still remain to be elucidated. Cells capture their own cytoplasm and organelles and consume them in lysosomes. The resulting breakdown products are inputs to cellular metabolism, through which they are used to generate energy and to build new proteins and membranes. Autophagy preserves the health of cells and tissues by replacing outdated and damaged cellular components with fresh ones. In starvation, it provides an internal source of nutrients for energy generation and, thus, survival. A powerful promoter of metabolic homeostasis at both the cellular and whole-animal level, autophagy prevents degenerative diseases. It does have a downside, however--cancer cells exploit it to survive in nutrient-poor tumors. However, the role of autophagy in cancer is complex and may differ depending on tumor type or context.

 
Pancreatic cancer is highly lethal disease. It is estimated that in 2010 more than 43,000 individuals in the United States have been diagnosed with this condition, and 36,800 have died from the disease. Most of these tumors tend to be therapeutically resistant against cytotoxic chemotherapies, targeted agents, and radiotherapy. Most common form of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which contains activating KRAS mutations in the great majority of cases, making this an ideal target for therapeutic intervention. Unfortunately, effective KRAS inhibitors have yet to be developed. The inhibition of pathways downstream from KRAS is a potentially viable approach to circumventing the difficulties in KRAS inhibition. However, KRAS has a multitude of effectors, many of which are poorly characterized, making it a significant challenge to completely shut off the KRAS pathway.

In their study Dr. Alec Kimmelman, MD, PhD, a radiation oncologist at Harvard Medical School, and his group demonstrated that pancreatic tumor derived cell lines and tumors isolated from patients with pancreatic cancers had activated autophagy. Cleaved form of LC3, a protein which associates with autophagosome membranes, widely used as a marker protein for autophagy in the field, was found to be over-expressed in these cells lines and primary tumors. Realizing that profuse activation of autophagy may contribute to pancreatic tumor growth, researchers designed an experiment in which they planned to treat the pancreatic cancer cell lines with Chloroquine, already known as inhibitor of autophagy. As a control, chloroquine was also used to treat normal cell lines with low expression of autophagy. Lo and behold, these researchers found that cell lines derived from pancreatic cancers which had higher level of autophagy were highly sensitive to autophagy inhibition by Chloroquine but this drug had minimal effects on those non cancerous cell lines which had lower levels of autophagy. In many other supporting experiments, researchers confirmed that in keeping with their elevated basal autophagy, pancreatic cancer derived cell lines exhibited a marked sensitivity to chloroquine.

However, apart from having a translational implication, this study must be taken as an indicator of levels of complexities of ongoing cellular processes inside a growing tumor. It is important to re-emphasize that autophagy may act to promote tumorigenesis in other types of cancer, but it may not be as prevalent or as pronounced as in pancreatic cancer, in which the overwhelming majority of tumors are dependent on this process. This study also warrants for further work to be performed to determine the specific roles of autophagy in other tumor types as it should not be forgotten that the positive role for autophagy in the maintenance of advanced pancreatic cancers stands in contrast to a number of other malignancies, in which genetic evidence from human specimens and mouse models shows that inactivation of autophagy can promote tumorigenesis.

The most important aspect of this study is that chloroquine and its derivatives which effectively inhibit autophagy, and in this study, inhibit pancreatic tumor growth—have been safely used in patients for many years as anti-malarial therapies. Given all these factors, we all should hope to see clinical trials to begin soon in pancreatic cancers using these drugs targeting autophagy.

Superbug in New Delhi

Antibiotic resistance is a type of drug resistance where microorganisms especially bacteria are able to survive exposure to an antibiotic. The primary cause of antibiotic resistance is genetic mutation in bacteria. The prevalence of antibiotic resistant bacteria is a result of unsupervised use of antibiotics or use of too many antibiotics by careless physicians without much rationale in order to treat the infection quickly. The greater the duration of exposure the greater the risk of the development of resistance irrespective of the severity of the need for antibiotics.  The production of β-lactamases in Gram-negative bacteria, is a serious bacterial resistance problem worldwide. If a bacterium carries one or several resistance genes, it is called, informally, a superbug or super bacterium. Antibiotic resistance poses a significant health problem, as in some cases, people infected with resistant bacteria can not be treated effectively by wide variety of antibiotics which could ultimately lead to fatalities.

Until late 90s, antibiotic resistance was not very fashionable beyond clinicians and researchers with first-hand knowledge of the topic. However, now that it is the focus of WHO's World Health Day on April 7, resistance has joined the front rank of global health concerns. What has brought antibiotic resistance into the limelight, and can this new-found status be harnessed to “safeguard these medicines for future generations”, to use the words of the World Health Day website? Recent studies have identified extended-spectrum β-lactamases in high proportions in enterobacteria from India; faced with this problem, the use of reserved antibiotics such as carbapenems has become necessary.

Last year, there was a study published in Lancet which reported the presence of superbug (antibiotic resistance bacteria) in the British patients that had been treated in India. It is important to note that India is fast becoming a hub for medical tourism given its cheaper and good quality health services especially for those who can not afford to have treatment in western health system due to financial constraints. However, government of India and several health experts in India rejected that study based on some technical flaws in the study and also because they thought this study could be biased and politically motivated to discourage rapidly growing health industry in India. Now this another study again by a British group, forces us to take this problem more seriously rather than rejecting as this time they reported the presence of NDM-1 β-lactamase-producing bacteria in environmental samples in New Delhi has important implications for people living in the city who are reliant on public water and sanitation facilities. Researchers collected samples by swabbing seepage water such as water pools in streets  and public tap water from sites within a 12 km radius of central New Delhi, with each site photographed and documented and then analyzing them for the presence of the NDM-1 gene, blaNDM-1, by molecular detection methods.

Though only small percentage of these samples were tested positive for superbug, implications of these results for people living in the Delhi city who are reliant on public water and sanitation facilities are far more serious. International surveillance of resistance, incorporating environmental sampling as well as examination of clinical isolates, needs to be established as a priority. Of course as true with many scientific studies, this study is also not flawless; as microbiologists can certainly comment on the technical issues, but no one would disagree that now health regulatory boards and health policy makers in the countries where they have no or less regulation on the use of antibiotics, should wake up and implement the necessary measures. It is a common practice in India (except few big metropolitan cities) that people go to a pharmacy and ask for an antibiotic of their choice to treat their common health problem, some of these short term health conditions  may not even need antibiotics as there is no bacterial infection yet such as seasonal cold/fever or viral gastroenteritis. This practice should immediately be stopped irrespective of results and intention of recent  Lancet study.  

http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(11)70059-7/abstract#

Nobel Prize Winner Baruch Blumberg who identified hepatitis B virus and later developed vaccine dies......

Asbestos and Risk of Cancer

Asbestos (from Greek ἄσβεστος or asbestinon, meaning "unquenchable" or "inextinguishable") is a set of six naturally occurring silicate minerals exploited commercially for their desirable physical properties. They all have in common their asbestiform habit, long, thin fibrous crystals. The inhalation of asbestos fibers can cause serious illnesses, including malignant lung cancer, mesothelioma (a type of cancer strongly associated with exposure to amphibole asbestos), and asbestosis (a type of pneumoconiosis). Long exposure to high concentrations of asbestos fibers is more likely to cause health problems, as asbestos exists in the ambient air at low levels, which itself does not cause health problems. The European Union has banned all use of asbestos and extraction, manufacture and processing of asbestos products.

 

Asbestos became increasingly popular among manufacturers and builders in the late 19th century because of its sound absorption, average tensile strength, and its resistance to heat, electrical and chemical damage. When asbestos is used for its resistance to fire or heat, the fibers are often mixed with cement or woven into fabric or mats. Asbestos was used in some products for its heat resistance, and in the past was used on electric oven and hotplate wiring for its electrical insulation at elevated temperature, and in buildings for its flame-retardant and insulating properties, tensile strength, flexibility, and resistance to chemicals.

Worldwide, at least 90 000 people die every year from illnesses resulting from occupational exposure to asbestos. However, this number only takes into account workers and ex-workers who have been identified with asbestos-related lung cancer, mesothelioma, and asbestosis. But asbestos has also been linked to laryngeal and ovarian cancer. Factor in asbestos-related illness among individuals whose work history has not been recorded, the family members of those who work with asbestos, and people living near asbestos factories and mines, and the death toll is much higher.


The lengthy latency period of asbestos-related malignant diseases—in some cases more than 40 years—means that even in countries that no longer use the material, the disease burden continues to rise. The UK, for example, banned all forms of asbestos in 1999 but at least 3500 people die from asbestos-related illnesses every year, and this figure is expected to increase to about 5000 in the coming years.
All of which has prompted more than 40 countries—including all member states of the European Union—to ban chrysotile. The World Bank has determined not to use it in any new development projects; and WHO has noted that “the most efficient way to eliminate asbestos-related disease is to stop using all types of asbestos”.



Nevertheless, about 125 million people across the globe are exposed to Asbestos in their working environment. Worldwide production remains at roughly the same level as in 1960: nearly 2·2 million metric tonnes per year. Vast development projects in Asia are largely responsible for maintaining the market. In particular, India’s asbestos industry is burgeoning. Only in first decade of 21^st century, the demand of asbestos in India has doubled from roughly 125 000 metric tonnes to about 300 000. Nearly all of India’s asbestos is mixed with cement to form roofing sheets. The health consequences especially rise in lung diseases in India are already well known, but for various political reasons, the cause behind this meteoric rise in lung diseases has never been attributed to the extensive use of asbestos or at least there has been no campaigns by government agencies to make people aware about the consequences of using this disastrous material. Though mesothelioma has never been documented as a major cancer in India, however we can not ignore the fact that current health system which is primarily under control of government of India, does not have sufficient resources to record death and diseases and most of the deaths due to any disease especially in rural areas go unnoticed and without proper diagnoses due to poor infrastructure in medical health.  Besides, there is nihilistic attitude prevailing among people as well health care providers towards cancer in India as it primarily victimizes older people.  Therefore I believe that there is a need for a real assessment of asbestos related diseases especially mesothelioma in order to achieve real statistics.



Also, it is important to notice that out of India’s 300 or so medical schools, few have a training program in occupational health. Out of several thousands of physicians in India, only few of them have had training in occupational health. Consequently, asbestosis is frequently misdiagnosed as tuberculosis or bronchitis. The latest cancer registry data have no information on mesothelioma. The health and safety legislation does not cover 93% of workers in the unorganized sector where asbestos exposures are extremely high. Workers remain uninformed and untrained in dealing with asbestos exposure. Enforcement agencies are not fully conscious of the risks of asbestos exposure. Industrial hygiene assessment is seldom carried out and pathologists do not receive training in identifying mesothelioma histopathologically. The lack of political will and powerful influence of the asbestos industry are pushing India toward a disaster of unimaginable proportion. Rapidly industrializing India is described by the International Monetary Fund as a young, disciplined, and vibrant economy with an average GDP of 8.6% for last 4 years. But now it is time to introspect and question: are Indians going to pay a heavy price in the terms of health for this rapidly growing economy???