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Black pepper, piperine and vitiligo

Black pepper, piperine and vitiligo – a personal history from Amala Soumyanath (née Amala Raman)

Amala Soumyanath led the research that discovered piperine as a potential treatment for vitiligo. Here she tells the story from her personal point of view and brings us up to date with current developments:

A Personal Passion: My First Introduction to Vitiligo

Amala Soumyanath, Ph.D.

My connection with vitiligo began on an ordinary working day at King's College London -  almost 20 years ago!  As a registered pharmacist with a Ph.D, I held a faculty position in the Department of Pharmacy, where I taught and led a research group in my favorite subject – pharmacognosy, the scientific study of medicinal agents from nature. One day, our of the blue, I received a telephone call from a "Maxine Whitton of the Vitiligo Society."  She stated that a member had received a Chinese herbal prescription with several named plants, and asked if I could find out if any of them might be estrogenic. I agreed to help, but the first thing I had to do was to look up what "vitiligo" was! I was surprised to discover that "vitiligo" was the name of a skin disorder that I had observed in multiple individuals. The condition is characterized by patches of depigmented skin, and I already knew of it by another name, "leucoderma." As a pharmacist and scientist studying medicinal plants I was immediately intrigued by the disease, its causes, and the fact that PUVA therapy for vitiligo, was based on psoralens which are derived from plants. I also learned that there was no really effective treatment for vitiligo. I decided right then to apply my scientific skills to search for a new treatment, and that this search would begin with plants used in traditional herbal medicine. Little did I know that I would go on to develop vitiligo myself, making my pursuit of a treatment more than just an interesting research project.


The Discovery of Piperine

 The first step was to research and compile a list of herbs described in different herbal medicine systems for the treatment of vitiligo. We focused on Ayurvedic and Chinese medicinal plants as these systems were well documented. The first graduate students to work on this project were Dania Kowalska and Zhixiu Lin. We obtained plant samples, made extracts of these herbs, and developed a method to test them for the ability to stimulate melanocyte (pigment cell) growth [1]. This property would be necessary to repigment vitiligo patches. The cells we used were mouse melan-a cells grown in culture dishes and were provided by Professor Dorothy Bennett, St. Georges Hospital, London an expert in melanocyte biology. Out of almost 30 herbs we tested- one extract stood out! A water extract of black pepper not only made the pigment cells grow faster, it also made them put out finger-like projections called dendrites which are important for their function in the skin. One component from black pepper, a compound called piperine, also showed the same effects [2]. In pharmaceutical parlance, piperine represented a "lead" molecule, one that could be developed, in original or modified form, for use in treating a disease.

Validating Piperine as a "Lead" Molecule

Our early work was supported by pilot grants from the Vitiligo Society UK and the Institute of Chinese Medicine, UK. A donation of £250 from the Gulam K Noon Foundation allowed us to buy a multichannel micropipettor, an essential piece of lab equipment! However, once we had our lead compound, I was able to raise substantially larger funding (£200,000) from BTG plc, a UK technology transfer company. My research also brought me into close contact with the Vitiligo Society UK. I was honored to serve the Society as a council member and secretary for a number of years. This valuable experience gave me a greater understanding of the issues and difficulties faced by people with vitiligo.

Over the next few years (1997–2002), we completed additional studies at King's College London, in which we made chemical variations (analogs) of piperine and tested them for their ability to stimulate melanocyte proliferation in culture dishes [3]. Two analogs of piperine, abbreviated to THP and RCHP, showed particularly good activity, so we then tested piperine, THP and RCHP for effects on skin pigmentation in mice. We were thrilled to find that all three compounds were able to stimulate the growth of pigment cells in a special strain of lightly pigmented mice, causing their skin to visibly darken. This effect was enhanced if we used UV light in addition to the compounds [4]. Essential to this research were collaborations I had established with Professor Robert Hider (a medicinal chemist) and Professor Antony Young (a photobiologist), and the dedication and hard work of Radhakrishnan Venkatasamy (a graduate student) and Dr. Laura Faas (a postdoctoral fellow). These studies allowed us to secure international patents for the use of piperine and its analogs to treat vitiligo.

Keeping the Vitiligo Fire Burning

black pepper

At this point, I had an exciting development in my personal life – I got married and relocated to the USA. I left King’s College London in late 2002, and found employment as a research faculty member in the Department of Neurology at Oregon Health & Science University (OHSU), Portland, Oregon. Although the emphasis of my research shifted to studying herbs used in neurological diseases, I had not forgotten piperine and vitiligo! The Department of Neurology Chair, Dr. Dennis Bourdette, was very supportive of my continuing this work, so I set about making contacts at OHSU who could help move the piperine project forward.

Having shown effectiveness in cells and in mouse skin earlier in London, my next goal was to move toward testing piperine in humans. OHSU incorporates a medical school, research centers, and most importantly, a hospital. The Department of Dermatology has a strong research focus, and I approached Dr. Andrew Blauvelt, who worked in that department, to support my efforts. This led to an introduction to dermatologists Dr. Eric Simpson and Dr. Ben Ehst, with whose help I developed a detailed plan (protocol) for a clinical trial of piperine in patients with vitiligo. However, prior to actually performing a clinical study, it was important to get more data on piperine's effects on human pigment cells, as opposed to cells from mouse skin. It was also important to investigate the safety of piperine when applied to the skin. Of particular relevance are piperine's effects on the development of melanoma (a pigment cell cancer). I was fortunate to find, and enlist the support of  Dr. Philippe Thuillier, an expert in skin cancer studies and an assistant professor at OHSU’s Department of Public Health and Preventive Medicine. Our experiments, funded by AdPharma, Inc., showed that piperine does indeed stimulate the replication of human melanocytes in culture, including those from uninvolved skin of a vitiligo patient. We used cell lines that were kindly provided by Dr. Caroline lePoole of Loyola University, Chicago. Piperine also stimulated human melanocytes when grown within a reconstructed skin model [5]. For this project we had excellent support from colleagues in OHSU's Biomedical Engineering and Dermatology departments (Professor Steven Jacques, Dr Kevin Phillips and Ravikant Samatham) who used innovative optical methods to image pigmentation and melanocytes in the skin models [6].

Significantly, and in agreement with other laboratories, we found that piperine has an inhibitory effect on cultured melanoma cells and prevents melanoma cell growth in a reconstructed full skin model [5]. To further this aspect of our study, we have introduced the HGF mouse model of melanoma (developed by the National Cancer Institute) to OHSU with the help of funds I raised from OCTRI (the Oregon Clinical and Translational Research Institute). We are presently studying the effects of piperine in this model with funding from the Department of Dermatology's Jesse Ettelson Fund for the Advancement of Dermatology Research. These ongoing studies are important to establish the safety of piperine.  


Heading for the Homestretch: Will Piperine work in humans?

In July 2013, this project received a tremendous boost with the appointment a new chair of dermatology, Professor Sancy Leachman. Dr. Leachman is a dermatologist and research scientist. Fortuitously for this project, Dr. Leachman is an expert in pigment cell biology, and has a particular interest in pigment cell disorders such as vitiligo and melanoma! She is extremely enthusiastic about this project and has pledged her commitment and expertise to developing piperine as a new treatment for vitiligo. As a bonus, she has also brought two additional team members on board. The first is Dr. Pamela Cassidy, a medicinal chemist with experience in skin culture techniques, and with the HGF mouse model of melanoma mentioned earlier. The second addition is Eric Smith, a talented scientist with expertise in the immunohistochemical evaluation of skin samples.

My Personal and Professional Commitment to Discovering a Treatment. Will Piperine Treat Vitiligo?

So, a simple phone call from Maxine Whitton (recently awarded an MBE for her services to vitiligo), the spark of an idea, and a good measure of commitment and persistence on my part have brought piperine to the brink of being tested in humans. It has been rewarding to apply my knowledge of the drug development process to such an exciting and potentially groundbreaking project. This has only been possible due to the support of all the excellent collaborators, postdoctoral fellows and students who have joined and supported my vision for piperine and vitiligo, with their unique areas of expertise. As mentioned earlier, my goal to develop piperine as a treatment for vitiligo has an additional personal impetus. In 2006, after a vacation in Central America, I too developed vitiligo. I now have noticeable patches on my face, hands and legs. I feel privileged that my research has led to new hope of a treatment for this difficult condition.  

I am determined to continue research on piperine and vitiligo – to evaluate its efficacy in humans and to understand more about its effects on melanocytes. The piperine project has attracted the dedication and commitment of a talented team of researchers at OHSU – a world renowned center with outstanding facilities for clinical and basic science research. At the project helm is Dr. Sancy Leachman, an experienced dermatologist and pigment cell expert, and has my continued dedication and scientific vision as initiator and ongoing champion of this project. If we are able to define how piperine works and to demonstrate the safety and efficacy of piperine in a small "proof of concept" human study, this would be sufficient to attract a large pharmaceutical company to move forward rapidly with a product for treating vitiligo. Sadly, the missing element is funding for these studies. We continue to approach standard funding sources, but response time is slow and resources are limited.  With this excellent team ready to get to work on this project, we hope to accelerate the pace of the project by reaching out to the general community  for funding.  Funds raised will support our ongoing studies on piperine at both the clinical and basic science levels. With the high incidence of vitiligo worldwide, donations of any size from those affected by this condition would soon add up and make a real difference to our rate of progress.

Donate to Vitiligo ResearchYou can support our research on piperine for vitiligo, by making an online donation to our Vitiligo Research FundExternal Link Icon.

I thank you in advance for your support.

Amala Soumayanath

References

  1. Lin ZX, Hoult JR, Raman A. Sulphorhodamine B assay for measuring proliferation of a pigmented melanocyte cell line and its application to the evaluation of crude drugs used in the treatment of vitiligo. J Ethnopharmacol 1999; 66(2): 141-150
  2. Lin Z et al. Stimulation of mouse melanocyte proliferation by Piper nigrum fruit extract and its main alkaloid, piperine. Planta Med 1999; 65(7): 600-603
  3. Venkatasamy R et al. Effects of piperine analogues on stimulation of melanocyte proliferation and melanocyte differentiation. Bioorg Med Chem 2004; 12(8): 1905-1920
  4. Faas L et al. In vivo evaluation of piperine and synthetic analogs as potential treatments for vitiligo using a sparsely pigmented mouse model. British Journal of Dermatology 2008; 158: 941-950
  5. Thuillier P et al. Effects of piperine on human melanocytes and melanoma cells in vitro. Manuscript prepared, awaiting submission.
  6. Samatham R et al, Progress in Biomedical Optics and Imaging - Proceedings of SPIE 7883 , art. no. 788309, 2011.