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denvernaturopathic.betulinicacidupdate

Betulinic Acid for Skin Cancer Update, and a mention of Santa Claus
December 21, 2006
Jacob Schor, ND

A year ago, I sent out a newsletter on betulinic acid and its potential use in treating cancer, especially melanoma. As it was almost Christmas when I sent it out, I managed a weak tie in to some trivia about Santa Claus. It turns out that our image of this generous gentleman may be a bit misplaced. Instead, I suggested that you consider Santa from an anthropological viewpoint, as a commercialized euphemistic representation of a mad eyed shaman of the reindeer people of the far north, stumbling across the frozen tundra feeding hallucinogenic amanita mushrooms to both his reindeer herds and his ‘congregation', dropping down the smoke holes of yurts with a psychedelicized ho-ho-ho.

I enjoyed reading up on this history and found it entertaining to contemplate when watching Santa Claus at the shopping mall. So entertained was I that I decided to resend the same newsletter out again this year.

My recent email on mistletoe and my allusions to our current culture wars over wishing a Merry Christmas, generated several requests from people asking to be removed from our mailing list. At this point, we hopefully won't offend anyone else on the list by revealing Santa's true identity.

First, we must look at new developments regarding betulinic acid since this time last year. Recall that betulinic acid is a chemical derived from Birch tree bark. A paper back in 1995 first suggested that betulinic acid might be useful in treating skin cancer. Last year's Santa newsletter chronicled the early studies. So what is new? It turns out that a lot is new.

In February 2006, a paper reported great success using a topical salve containing betulinic acid to treat actinic keratosis. Twenty-eight patients were treated with either betulinic alone or betulinic acid in combination with standard freezing therapy. Clearing of more than 75 % of the lesions was seen in 79 % of the patients treated with birch bark ointment alone. The response rate of the combined treatment, betulinic acid and freezing, was 93 %. [i]

Studies are looking into the chemical structure of various betulinic derivatives attempting to figure out which forms work best against which cancer types and, more important to drug companies, which ‘analogues' that can be patented also work. A study from May, details the variations on structure hoping to determine which pieces are most needed to produce the substance's anticancer effect for modeling chemotherapy drugs after. [ii] A study from September is already testing analogues to betulinic acid to see if they work as well as the real stuff. [iii]

Half a dozen or so other studies continue to pursue information on betulinic acid's value in treating skin and other cancers. Betulinic acid kills other types of cancer cells as well as melanoma.

In a study published December 12, that is last week, Dutch researchers, “… tested the in vitro sensitivity of broad cell line panels derived from lung, colorectal, breast, prostate and cervical cancer, which are the prevalent cancer types characterized with highest mortalities in woman and men.” Their results were impressive: “….in all cell lines tested colony formation was completely halted at remarkably equal BA concentrations that are likely attainable in vivo.” [iv]

It was effective against all the cell lines tested in that study but they stuck with the big cancers. Another study published earlier in the year, suggests betulinic acid does not work against all types of Burkitt's lymphoma, one of those obscure things you don't want to get. [v]

Other uses for betulinic acid are showing up in the literature. It may be useful as an anti inflammatory and in killing the HIV virus that causes AIDs. It still appears to be safe, it is non toxic in mice in doses up to 500 mg per kilogram. [vi]

Last year I mentioned studies that showed that betulinic acid augmented the anticancer effect of vitamin D on leukemia, vincristin on lung cancer, hyperthermia and several other anticancer drugs. A study from September 2005, which I hadn't noticed, reports that betulinic acid was helpful when used in combination with vincristin for treating squamous cell cancers of the head and neck. [vii]
Just in November, a Chinese group reported a newer simpler and less expensive way to extract betulinic acid. [viii] Back in January, an American company named NATURNORTH TECHNOLOGIES near Duluth , Minnesota reported they had figured out a way to make betulinic acid from waste materials leftover from paper manufacturing. [ix]
Despite this interesting research, betulinic acid is still not widely available. I have yet to see any of our major nutritional supplement suppliers offering it in capsule or topical form. At this point, betulinic is available from chemical supply houses at reasonable prices and we have the option of hand compounding it into topical ointments or encapsulating it ourselves. Another option is to use Birch bark which can contain as much as 30% betulin. This can be made into a tea or a compress.
My imagination quickly runs to the idea of steeping pounds of birch bark in a hot tub in which we then soak patients. Given the apparent safety of the treatment and the current prognosis for patients with melanoma, one has to ask, “Why not?”

I will paste our original Santa newsletter below. You can read it with references on our website: http://denvernaturopathic.com/news/santaandbetulinic.html


Santa Claus, Hallucinogenic mushrooms, birch trees and melanoma
December 8, 2005
Subject: Betulinic acid research is moving forward confirming its value in treating melanoma. Chaga mushrooms may be even more useful. Santa Claus trivia as well.


It is time to review the new studies on betulinic acid, a derivative of birch bark, and its potential role in treating melanoma. It is also time to consider the use of Chaga mushrooms which grow on birch trees. Yet given the season, we first must consider Santa Claus and his reindeer as the subjects are connected.

Santa Claus and Amanita Mushrooms:
Our dear Santa, despite his modern association with Christmas, is apparently modeled after the shamans of the reindeer culture of the far northern latitudes. These peoples and especially their shamans relied on amanita mushrooms for their potent hallucinogenic properties which proved efficacious for communing with the gods.

Amanita muscaria mushrooms grow only under certain types of trees, mostly firs and evergreens. Amanita are bright red with white spots: they are the original bright gifts that these early people sought under their ‘Christmas' tree.

In the belief system of these people, the sacred North Star stood atop a magical evergreen tree that was the central axis of the world. The shaman would metaphorically climb this tree and, by touching the North Star, would pass into the realm of the gods. With enough hallucinogenic mushrooms, anything is possible.

There is a drawback. Amanita mushrooms are very poisonous. They cause catastrophic liver failure. Serious shamans could avoid violent death by slowly building up tolerance to the poison by consuming tiny amounts of mushroom daily. Daily doses of violently toxic hallucinogens have their drawbacks. You can't hold a day job.

For the peoples of the far north reindeer provided an almost magical way around amanita toxicity. Reindeer are unaffected by the toxins or hallucinogens in amanita. When reindeer eat the mushrooms, the active hallucinogenic chemicals are left unchanged but the toxic elements are inactivated. By feeding mushrooms to the reindeer and then collecting and drinking the reindeer urine, our early Santa found a simple chemical detoxification process. If this sounds gross, recall how Premarin is made.

If you are into trivia, some scholars think that the origin of the phrase "to get pissed," was started by this urine-drinking; it preceded the consumption of alcohol by thousands of years and left the consumer incredibly plastered.

Does the image of an ancient shaman dressed in his traditional red fur hat trimmed with fur and long black leather boots coming back from collecting mushrooms carrying large sacks of bright red ‘gifts' sound a bit like the fellow in Coca-cola ads?

The hallucinogenic effect of the amanita mushroom often includes the feeling of flying, which probably accounts for the image of bell decked reindeer flying around the North Pole with a hallucinating shaman laughing in his sled.

While pondering that ancient Santa stumbling stoned on reindeer piss and falling through the smoke hole of his yurt, come back to the subject of betulinic acid which is what this article is really about.

Birch Trees and Betulinic Acid:
Betulinic acid is found in birch tree bark. These trees inhabit the northern cold latitudes and were very familiar to the reindeer peoples of northern Europe and Asia . Over the last few years a growing body of published scientific research has made this chemical appear very interesting for its potential effect in cancer treatment.

Although birch bark has a long history of use in making various herbal medicines, modern interest didn't start until ten years ago. In March, 1995, John Pezzuto of the University of Illinois , Chicago reported that a compound isolated from birch bark called betulinic acid, was able to kill human melanoma cells transplanted into mice.

Dr. Pezzuto extracted betulin from birch logs found in an old woodpile near his Chicago laboratory and converted this into betulinic acid (BA). Unlike conventional chemotherapy, this compound caused no apparent side effects and, for obvious reasons, is potentially very inexpensive. This initial research spurred a flurry of studies confirming the initial findings, delineating the chemical mechanisms of action, or at least some of them, and finding BA effective at killing other types of cancer cell besides melanoma.

Studies published in the last few years continue to confirm betulinic acid (BA) kills melanoma cells. Eight years after the original article from 1995 [i] the original research group published again, providing greater detail to the mechanism of action. [ii] Various chemical derivatives of BA have been created and examined with even greater cytotoxicity, 2005. [iii] [iv] [v] [vi]While toxic to skin cancer cells BA encourages cell differentiation in normal skin cells according to a 2005 study. [vii]
Betulinic acid may be useful in treating other cancers besides melanoma. Research has been published suggesting use of BA in treatment of leukemia, [viii] [ix] lung, [x] head and neck cancer, [xi] and brain [xii] cancer. It enhances the effect of other treatments, including vitamin D on leukemia, [xiii]vincristine on lung cancer, [xiv] hyperthermia [xv] and potentiates other anticancer drugs. [xvi]
Doctrine of Signatures and Chaga Mushroom:
There is an old theory in herbal medicine called the Doctrine of Signatures which suggests that the therapeutic use of a plant can be inferred from the image, shape or form the plant presents. In simpler word, the plant's appearance contains a message which suggests the organ or illness it is useful to treat. It is interesting that the skin of the birch tree yields a chemical useful in treating skin ailments. It is even more interesting if you look at the appearance of a fungus that occasionally grows on birch trees. This fungus, a mushroom polyspore called Chaga, Innonotus obliquus , which parasitizes birch trees and can only be described as looking like a tumor. The Chaga mushroom has been revered by those same reindeer cultures that brought us Santa, and used as a medicine to treat among other things, skin cancers. Although the mushroom can grow on other trees, including alder and beech, only the mushrooms from birch trees are reputed to have medicinal value.
Unlike most mushrooms, chaga is a polypore, a fungus with pores instead of gills. Chaga is a parasite and draws its nutrients out of living trees, rather than from the ground. Fungi digest food outside their bodies by releasing enzymes into the surrounding environment, breaking down organic matter into a form the fungus can then absorb. Chaga absorb large amounts of betulinic acid from the birch trees and convert it into various forms that can be ingested orally.
Chaga mushrooms are not easy to come by. They often grow high in the trees at a height of 10 to 30 feet, which makes collecting difficult. The Russians, the main commercial source of these mushrooms, go out with ropes and harnesses. The ideal chaga fruiting body is 25 years old and may weigh 10 pounds. According to one chaga website, only one birch tree in 15,000 yields a mushroom.
There is less research on Chaga than on betulinic acid yet what there is looks promising. Chaga is immunostimulating, having effects similar to other medicinal mushrooms. [xvii] It has anti-inflammatory and pain relieving action. [xviii] It acts as an antioxidant, [xix] preventing damage to cell DNA. [xx]

What does this have to do with Santa and his reindeer? Not much. Reindeer convert one medicinal plant substance into another more ‘beneficial' for people. This sort of transformation by an intermediary organism into something more useful to people is not unique. The fermentation of sugars by yeast to make alcohol is the most obvious example. The biotransformation of birch bark by Chaga mushrooms may yield a unique ally in the treatment of specific illnesses. Betulinic acid appears useful on its own yet we already know that certain chemical derivatives are even more powerful. Chaga may provide a source of betulinic acid at once both more bioavailable and useful. These mushrooms may provide benefits, in ways more complex and more elegant than the research scientists have yet to figure out? If nothing else the digression about Santa should provide food for thought this holiday season.

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Note: In 1994 local Denver artist, Tom Stimson traveled extensively documenting the shamanic use of Amanita mushrooms in far eastern Russia . He produced and sells a fascinating video on these Siberian shamans who still employ amanita mushrroms. http://pageformer.com/mukomor/




References 





[i] Nature Medicine 1, 1046 - 1051 (1995)
Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis
Emily Pisha1, Heebyung Chai1, Ik-Soo Lee1, Tangai E. Chagwedera2, Norman R. Farnsworth1, Geoffrey A. Cordell1, Christopher W.W. Beecher1, Harry H.S. Fong1, A. Douglas Kinghorn1, Daniel M. Brown3, 5, Mansukh C. Wani3, Monroe E. Wall3, Tina J. Hieken4, Tapas K. Das Gupta4 & John M. Pezzuto1, 4, 6
As a result of bioassay-guided fractionation, betulinic acid, a pentacyclic triterpene, was identified as a melanoma-specific cytotoxic agent. In follow-up studies conducted with athymic mice carrying human melanomas, tumour growth was completely inhibited without toxicity. As judged by a variety of cellular responses, antitumour activity was mediated by the induction of apoptosis. Betulinic acid is inexpensive and available in abundant supply from common natural sources, notably the bark of white birch trees. The compound is currently undergoing preciinicai development for the treatment or prevention of malignant melanoma.

Clin Cancer Res. 2003 Jul;9(7):2866-75.
Click here to read  
Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation. 


Tan Y , Yu R , Pezzuto JM . 

Program for Collaborative Research in the Pharmaceutical Sciences, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois 60612, USA. 

Betulinic acid, a naturally occurring triterpene found in the bark of the white birch tree, has been demonstrated to induce programmed cell death with melanoma and certain neuroectodermal tumor cells. We demonstrate currently that treatment of cultured UISO-Mel-1 (human melanoma cells) with betulinic acid leads to the activation of p38 and stress activated protein kinase/c-Jun NH(2)-terminal kinase [widely accepted proapoptotic mitogen-activated protein kinases (MAPKs)] with no change in the phosphorylation of extracellular signal-regulated kinases (antiapoptotic MAPK). Moreover, these results support a link between the MAPKs and reactive oxygen species (ROS). As demonstrated previously, cells treated with betulinic acid generate ROS. Preincubation of cells with antioxidants blocks the process of programmed cell death, and prevents the phosphorylation of p38 and stress activated protein kinase/c-Jun NH(2)-terminal kinase. These data suggest that ROS act upstream of the MAPKs in the signaling pathway of betulinic acid. In addition to mediating these responses, treatment of cells with betulinic acid resulted in a gradual depolarization of mitochondrial membrane potential, a phenomenon established to contribute to the induction of programmed cell death. Interestingly, p38 was capable of partially modulating this perturbation, and investigations of mitochondria-associated apoptotic events indicate no involvement of known caspases. These data provide additional insight in regard to the mechanism by which betulinic acid induces programmed cell death in cultured human melanoma cells, and it likely that similar responses contribute to the antitumor effect mediated with human melanoma carried in athymic mice. 

PMID: 12855667 [PubMed - indexed for MEDLINE]

Bioorg Med Chem. 2005 May 16;13(10):3447-54.
Click here to read  
Synthesis of phthalates of betulinic acid and betulin with cytotoxic activity. 

Kvasnica M , Sarek J , Klinotova E , Dzubak P , Hajduch M . 

Department of Organic and Nuclear Chemistry, Faculty of Science, Charles University in Prague , Hlavova 8, 128 43 Prague 2, Czech Republic . 

Synthesis of 3beta-O-phthalic esters from betulinic acid and its esters and synthesis of phthalic esters from betulin and its monoacetates using classical acylation procedure with phthalic anhydride. The evaluation of cytotoxicity of the prepared compounds was using numbers of tumor cell lines in MTT test. It was discovered that hemiphthalic esters had better cytotoxicity than starting compounds as betulinic acid or quite inactive betulin. 

PMID: 15848757 [PubMed - indexed for MEDLINE]

Bioorg Khim. 2005 May-Jun;31(3):320-5.

[Synthesis and antitumor activity of cyclopropane derivatives of betulinic and betulonic acids] 

[Article in Russian] 

New cyclopropane derivatives of betulin were synthesized by attachment of dichlorocarbenes or dibromocarbenes to the double bond of betulin diacetate, followed by the deprotection of hydroxyl groups. The betulin cyclopropane derivative was obtained from 20,29-dihydro-20,29-dichloromethylenebetulin by treatment with lithium in tert-butanol. These compounds were converted into the corresponding derivatives of betulonic acid by oxidation with chromium trioxide. The reduction of oxo group with sodium borohydride led to the corresponding derivatives of betulinic acid. 20,29-Dihydro-20,29-dichloromethylenebetulinic acid proved to be the most cytotoxic toward human melanoma of the Colo 38 and Bro lines and human ovarian carcinoma of the CaOv line (IC50 10 microM). 20,29-Dihydro-20,29-dibromomethylenebetulinic acid inhibited the growth of the Bro melanoma cell line and the CaOv carcinoma cell line practically by 50% at a concentration of 10 microM. The other derivatives of betulinic and betulonic acids were active toward all of the three cancer cell lines at concentrations higher than 10 microM. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 3; see also http://www.maik.ru. 

PMID: 16004391 [PubMed - indexed for MEDLINE]



J Nat Prod. 2004 Jul;67(7):1100-5.
Click here to read  
Synthesis of A-seco derivatives of betulinic acid with cytotoxic activity. 

Urban M , Sarek J , Klinot J , Korinkova G , Hajduch M . 

Department of Organic and Nuclear Chemistry, Faculty of Science, Charles University in Prague , Hlavova 8, 128 43 Prague 2, Czech Republic . 

In this study, the relationships between the chemical structure and cytotoxic activity of betulinic acid (1) derivatives were investigated. Eight lupane derivatives (1-8), one of them new (6), five diosphenols (9-13), four of them new (10-13), two new norderivatives (14 and 15), five seco derivatives (16-20), four of them new (16, 17, 19, and 20), and three new seco-anhydrides (21-23) were synthesized from 1, and their activities were compared with the activities of known compounds. The effects of substitution on the A-ring and esterification of the carboxyl group in position 28 on cytotoxicity were of special interest. Significant cytotoxic activity against the T-lymphoblastic leukemia cell line CEM was found in diosphenols 9 and 13 (TCS(50) 4 and 5 micromol/L) and seco-anhydrides 22 and 23 (TCS(50) 7 and 6 micromol/L). All compounds were also tested on cancer cell lines HT 29, K562, K562 Tax, and PC-3, and these confirmed activity of diosphenols 9, 10, and 11 and anhydride 22. Diosphenols, as the most promising group of derivatives, were further tested on four more lines (A 549, DU 145, MCF 7, SK-Mel2). 

PMID: 15270560 [PubMed - indexed for MEDLINE]

Eur J Pharmacol. 2004 Sep 13;498(1-3):71-8.
  
Apoptotic activity of betulinic acid derivatives on murine melanoma B16 cell line. 

Liu WK , Ho JC , Cheung FW , Liu BP , Ye WC , Che CT . 

Department of Anatomy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People's Republic of China. ken-liu@cuhk.edu.hk 

The mitochondrion plays a crucial role in the process of apoptosis and has thus become one of the targets for the search for potential chemotherapeutic agents. Betulinic acid [3beta-hydroxy-lup-20(19)lupaen-28-carbonic acid], a lupane-type triterpene which is abundant in many plant species, has been shown to exert a direct effect on the mitochondria and subsequent apoptosis in melanoma cells. Chemical synthesis and modification of betulinic acid are being explored to develop more potent derivatives. We present here the apoptotic activity of several natural derivatives of betulinic acid which were isolated from the roots of a Chinese medicinal herb, Pulsatilla chinensis (Bge) Regel [Ye, W., Ji, N.N., Zhao, S.X., Liu, J.H., Ye, T., McKervey, M.A., Stevenson, P., 1996. Triterpenoids from Pulsatilla chinensis. Phytochemistry 42, 799-802]. Of the five compounds tested, 3-oxo-23-hydroxybetulinic acid was the most cytotoxic on murine melanoma B16 cells (IC50=22.5 microg/ml), followed by 23-hydroxybetulinic acid and betulinic acid (IC50=32 and 76 microg/ml, respectively), with lupeol and betulin exhibiting the weakest cytotoxicity (IC50> or =100 microg/ml). Exposure of B16 cells to betulinic acid, 23-hydroxybetulinic acid and 3-oxo-23-hydroxybetulinic acid caused a rapid increase in reactive oxidative species production and a concomitant dissipation of mitochondrial membrane potential in a dose- and time-dependent manner, which resulted in cell apoptosis, as demonstrated by fluorescence microscopy, gel electrophoresis and flow-cytometric analysis. Cell cycle analysis further demonstrated that both 3-oxo-23-hydroxybetulinic acid and 23-hydroxybetulinic acid dramatically increased DNA fragmentation at the expense of G1 cells at doses as low as 12.5 and 25 microg/ml, respectively, thereby showing their potent apoptotic properties. Our results showed that hydroxylation at the C3 position of betulinic acid is likely to enhance the apoptotic activity of betulinic acid derivatives (23-hydroxybetulinic acid and 3-oxo-23-hydroxybetulinic acid) on murine melanoma B16 cells. 

PMID: 15363977 [PubMed - indexed for MEDLINE]


Exp Dermatol. 2005 Oct;14(10):736-43.

  
Betulinic acid induces apoptosis in skin cancer cells and differentiation in normal human keratinocytes. 

Faculty of Pharmacy, Institute of Pharmaceutical Biology and Pharmacology, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany . 

Betulinic acid (BA), a pentacyclic triterpene of plant origin, induces cell death in melanoma cells and other malignant cells of neuroectodermal origin. Little is known about additional biological effects in normal target cells. We show, in this study, that BA induces differentiation as well as cell death in normal human keratinocytes (NHK). Cytotoxicity profiles of BA are compared among normal human keratinocytes, HaCaT cells, IGR1 melanoma cells and normal melanocytes. As expected, BA is toxic to all cell types, normal and malignant, but varies in its cytotoxic potency and in the extent of induction of apoptotic vs. necrotic cell death in the four different skin cell types. Apoptosis is proved by annexin V and Apo2.7 binding and by DNA fragmentation. Induction of differentiation-associated antigens in keratinocytes--filaggrin and involucrin--is demonstrated, together with specific morphological changes in treated cell cultures. BA, apart from its cytotoxic activities in cellular systems, is capable of inducing differentiation of NHK into corneocytes without immediately provoking apoptotic cell death. 

PMID: 16176281 [PubMed - indexed for MEDLINE]

Leukemia. 2004 Aug;18(8):1406-12.

  
Betulinic acid-induced apoptosis in leukemia cells. 

Department of Oncology/Hematology, Dr von Haunersches Kinderspital, Lindwurmstr 4, Munchen , Germany . 

Betulinic acid (BA), a natural component isolated from Birch trees, effectively induces apoptosis in neuroectodermal and epithelial tumor cells and exerts little toxicity in animal trials. Here, we show that BA-induced marked apoptosis in 65% of primary pediatric acute leukemia cells and all leukemia cell lines tested. When compared for in vitro efficiency with conventionally used cytotoxic drugs, BA was more potent than nine out of 10 standard therapeutics and especially efficient in tumor relapse. No crossresistances were found between BA and any cytotoxic drug. Intracellular apoptosis signaling in leukemia tumor cells paralleled the pathway found in neuroectodermal cells involving caspases, but not death receptors. In isolated mitochondria, BA induced release of both cytochrome c and Smac. Taken together, BA potently induces apoptosis in leukemia cells and should be further evaluated as a future drug to treat leukemia
Toxicol Lett. 2005 Mar 15;155(3):343-51.

  
Betulinic acid induces apoptosis in human chronic myelogenous leukemia (CML) cell line K-562 without altering the levels of Bcr-Abl. 

Raghuvar Gopal DV , Narkar AA , Badrinath Y , Mishra KP , Joshi DS . 

Laboratory Nuclear Medicine Section, Isotope Group, BARC, C/o Tata Memorial Hospital Annexe, Jerbai Wadia Road, Parel, Mumbai 400012, India. 

Betulinic acid (BA), a plant derived triterpenoid, isolated from various sources shows cytotoxicity in cell lines of melanoma, neuroectodermal and malignant brain tumors. Chronic myelogenous leukemia (CML) is characterized by Philadelphia chromosome (Bcr-Abl), a molecular abnormality leading to the intrinsic tyrosine kinase activity that provides growth and survival advantage to the cells. Present study describes the cytotoxicity of BA on human CML cell line K-562, positive for Bcr-Abl. The decrease in the viability of K-562 cells treated with BA at different concentrations and time intervals was assessed using MTT assay. Cell death induced by BA was determined to be apoptotic as measured by FACS analysis of PI stained nuclei, PS externalization by Annexin-V fluorescence and characteristic DNA fragmentation. DiOC6(3) fluorescent probe determined alterations in the mitochondrial membrane potential (MMP). RT-PCR confirmed the expression levels of Bcr-Abl in controls and K-562 cells treated with BA. The rapid loss of MMP of K-562 cells upon treatment with BA shows the direct activation of apoptosis at the level of mitochondria, overcoming the resistance of the high levels of expression of Bcr-Abl. 

PMID: 15649617 [PubMed - indexed for MEDLINE]

Br J Cancer. 2004 Apr 19;90(8):1672-8.

  
Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice. 

Department of Oncological and Regenerative Surgery, School of Medicine , The University of Tokushima , Tokushima 770-8503, Japan . 

We examined the antitumour effect of a combination of betulinic acid (BA) and vincristine (VCR) on murine melanoma B16F10 cells in vitro and in vivo. Betulinic acid, a pentacyclic triterpene, showed a synergistic cytotoxic effect on melanoma cells by combinational use of VCR. Betulinic acid and VCR induced cell cycle arrest at different points (BA at G1 phase and VCR at G2/M phase) and caused apoptosis in B16F10 melanoma cells. In the in vivo study, VCR inhibited metastasis of tumour cells to the lung. The addition of BA to VCR augmented suppression of the experimental lung metastasis of melanoma cells in C57BL/6 mice. The number of lung nodules of more than 1 mm in diameter in mice treated with BA and VCR was less than that in mice treated with VCR alone. These results suggest that BA is an effective supplement for enhancing the chemotherapeutic effect on malignant melanoma. 

PMID: 15083202 [PubMed - indexed for MEDLINE]


Head Neck. 2003 Sep;25(9):732-40.

  
Betulinic acid: a new cytotoxic compound against malignant head and neck cancer cells. 

Thurnher D , Turhani D , Pelzmann M , Wannemacher B , Knerer B , Formanek M , Wacheck V , Selzer E . 

Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Vienna, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. dietmar.thrunher@univie.ac.at 

BACKGROUND: A new compound, betulinic acid, has been found to be cytotoxic against a variety of tumor cells originating from the neural crest. Its efficacy against head and neck squamous cellular carcinoma cell lines has so far not been tested. METHODS: Cell numbers were assayed by automated counting; caspase activation and programmed cell death were determined using an antibody specific for an apoptosis-associated epitope in epithelial cells. The expression pattern of Bcl-2 family members was assessed by Western blotting. RESULTS: In two HNSCC cell lines betulinic acid induced apoptosis, which was characterized by a dose-dependent reduction in cell numbers, emergence of apoptotic cells, and an increase in caspase activity. Western blot analysis of the expression of various Bcl-2 family members in betulinic acid-treated cells showed, surprisingly, a suppression of the expression of the proapoptotic protein Bax but no changes in Mcl-1 or Bcl-2 expression. CONCLUSION: These data clearly demonstrate for the first time that betulinic acid has apoptotic activity against HNSCC cells. Copyright 2003 Wiley Periodicals, Inc. Head Neck 25: 732-740, 2003 

PMID: 12953308 [PubMed - indexed for MEDLINE]

Acta Neurochir (Wien). 2004 Jul;146(7):721-9. Epub 2004 May 21.

  
Cell death induction by betulinic acid, ceramide and TRAIL in primary glioblastoma multiforme cells. 

Dr. von Haunersches Kinderspital, Munich , Germany . I.Jeremias@lrz.uni-muenchen.de 

BACKGROUND: Glioblastoma multiforme (WHO Grade IV, GBM) is the most malignant brain tumour with a mean survival time of less than one year. Betulinic acid, ceramide and TRAIL (TNF-related apoptosis inducing ligand) represent novel therapeutic agents for potential use in GBM. METHOD: Primary GBM cells of 21 patients with macroscopically complete tumour resection were tested in vitro for cell death induction by betulinic acid, ceramide, TRAIL and established therapeutics (BCNU, cisplatin, doxorubicin, vincristin and gamma-irradiation). FINDINGS: At peak plasma concentrations (PPC), Betulinic acid, ceramide and TRAIL induced cell death in primary GBM cells at higher rates than established cytotoxic drugs. Specific cell death > or =75% was observed in 43% (9/21), 38% (8/21), and 19% (4/21) for betulinic acid, ceramide, and TRAIL respectively, while this was only found in 5% (1/21) of gamma-irradiated and cisplatin-treated cells, and in none of the GBM cultures, where BCNU or vincristin were applied in PPC. CONCLUSION: Due to a markedly improved cell death of GBM cells as compared with established therapeutics, Betulinic acid, ceramide and TRAIL might represent potent substances for future treatment of GBM. 

PMID: 15197616 [PubMed - indexed for MEDLINE]

[xiii] Betulinic acid enhances 1a,25-dihydroxyvitamin D3-induced differentiation in human HL-60 promyelocytic leukemia cells
Ka-Hung Poon, Jinxia Zhang, Cheng Wang, Anfernee Kai-Wing Tse, Chi-Keung Wan, Wang-Fun Fong
Bioactive Products Research Group
Published at: Anti-cancer Drugs July 2004
Br J Cancer. 2004 Apr 19;90(8):1672-8.

  
Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice. 

Department of Oncological and Regenerative Surgery, School of Medicine , The University of Tokushima , Tokushima 770-8503, Japan . 

We examined the antitumour effect of a combination of betulinic acid (BA) and vincristine (VCR) on murine melanoma B16F10 cells in vitro and in vivo. Betulinic acid, a pentacyclic triterpene, showed a synergistic cytotoxic effect on melanoma cells by combinational use of VCR. Betulinic acid and VCR induced cell cycle arrest at different points (BA at G1 phase and VCR at G2/M phase) and caused apoptosis in B16F10 melanoma cells. In the in vivo study, VCR inhibited metastasis of tumour cells to the lung. The addition of BA to VCR augmented suppression of the experimental lung metastasis of melanoma cells in C57BL/6 mice. The number of lung nodules of more than 1 mm in diameter in mice treated with BA and VCR was less than that in mice treated with VCR alone. These results suggest that BA is an effective supplement for enhancing the chemotherapeutic effect on malignant melanoma. 

PMID: 15083202 [PubMed - indexed for MEDLINE]


[xv] minimal effect in normal tissues growing at pH 7.3.
Int J Hyperthermia. 2002 Mar-Apr;18(2):153-64.

Betulinic acid sensitization of low pH adapted human melanoma cells to hyperthermia. 

Wachsberger PR , Burd R , Wahl ML , Leeper DB . 

Department of Radiation
Oncology, Kimmel Cancer Center and Thomas Jefferson University , Philadelphia , PA 19107 , USA . phyllis.wachsberger@mail.tju.edu 

Betulinic acid is a known inducer of apoptosis in human melanoma that is most effective under conditions of low pH. It was hypothesized that betulinic acid, in combination with acute acidification and/or hyperthermia, would induce higher levels of apoptosis and cytotoxicity in low pH-adapted human melanoma cells than in cells grown at pH 7.3. DB-1 human melanoma cells, adapted to a tumour-like growth pH of 6.7, were exposed to hyperthermia (2h at 42 degrees C) and/or betulinic acid (4-10 microg/ml) and compared with cells grown at a physiological pH of 7.3 or after acute acidification from pH 7.3-6.3 or pH 6.7-6.3. Betulinic acid induced higher levels of apoptosis and cytotoxicity in low pH-adapted cells than in cells grown at pH 7.3, as measured by the terminal deoxynucleotidyl transferase (TdT) DNA fragmentation assay (TUNEL), the MTS cell viability assay, and single cell survival. Acute acidification of low pH adapted cells rendered them more susceptible to betulinic acid-induced apoptosis and cytotoxicity. In the presence of hyperthermia at 42 degrees C for 2 h, cells grown at pH 7.3 were not sensitized to heat killing by betulinic acid, whereas cells grown at pH 7.3 and acutely acidified to pH 6.3, cells adapted to growth at pH 6.7 and cells adapted to growth at pH 6.7 and acutely acidified to pH 6.3 were all similarly sensitized to heat killing by betulinic acid, with survival values of 5, 9 and 2%, respectively. It is concluded that betulinic acid may be useful in potentiating the therapeutic efficacy of hyperthermia as a cytotoxic agent in acidotic areas of tumours with minimal effect in normal tissues growing at pH 7.3.
•  [xvi]
Neoplasia. 2005 Feb;7(2):162-70.

  
Sensitization for anticancer drug-induced apoptosis by betulinic Acid. 

Fulda S , Debatin KM . 

University Children's Hospital, Prittwitzstrasse 43, Ulm 89075 , Germany .
simone.fulda@medizin.uni-ulm.de 

We previously described that betulinic acid (BetA), a naturally occurring pentacyclic triterpenoid, induces apoptosis in tumor cells through the mitochondrial pathway. Here, for the first time, we provide evidence that BetA cooperated with anticancer drugs to induce apoptosis and to inhibit clonogenic survival of tumor cells. Combined treatment with BetA and anticancer drugs acted in concert to induce loss of mitochondrial membrane potential and the release of cytochrome c and Smac from mitochondria, resulting in activation of caspases and apoptosis. Overexpression of Bcl-2, which blocked mitochondrial perturbations, also inhibited the cooperative effect of BetA and anticancer drugs, indicating that cooperative interaction involved the mitochondrial pathway. Notably, cooperation of BetA and anticancer drugs was found for various cytotoxic compounds with different modes of action (e.g., doxorubicin, cisplatin, Taxol, VP16, or actino-mycin D). Importantly, BetA and anticancer drugs cooperated to induce apoptosis in different tumor cell lines, including p53 mutant cells, and also in primary tumor cells, but not in human fibroblasts indicating some tumor specificity. These findings indicate that using BetA as sensitizer in chemotherapy-based combination regimens may be a novel strategy to enhance the efficacy of anticancer therapy, which warrants further investigation. 

PMID: 15802021 [PubMed - indexed for MEDLINE]

[xvii] Kim YO, Han SB, Lee HW, Ahn HJ, Yoon YD, Jung JK, Kim HM, Shin CS.
Immuno-stimulating effect of the endo-polysaccharide produced by submerged culture of Inonotus obliquus.
Life Sci. 2005 Sep 23;77(19):2438-56.
PMID: 15970296 [PubMed - indexed for MEDLINE]

[xviii] Park YM, Won JH, Kim YH, Choi JW, Park HJ, Lee KT.
In vivo and in vitro anti-inflammatory and anti-nociceptive effects of the methanol extract of Inonotus obliquus.
J Ethnopharmacol. 2005 Oct 3;101(1-3):120-8.
PMID: 15905055 [PubMed - in process]
[xix] Cui Y, Kim DS, Park KC. Antioxidant effect of Inonotus obliquus.
J Ethnopharmacol. 2005 Jan 4;96(1-2):79-85.
PMID: 15588653 [PubMed - indexed for MEDLINE]
[xx] Park YK , Lee HB, Jeon EJ, Jung HS, Kang MH.
Chaga mushroom extract inhibits oxidative DNA damage in human lymphocytes as assessed by comet assay.
Biofactors. 2004;21(1-4):109-12.
PMID: 15630179 [PubMed - indexed for MEDLINE]

[i] : J Dtsch Dermatol Ges. 2006 Feb;4(2):132-6.

[Treatment of actinic keratoses with birch bark extract: a pilot study]

[Article in German]
•  Huyke C ,
•  Laszczyk M ,
•  Scheffler A ,
•  Ernst R ,
•  Schempp CM .
Universitats-Hautklinik, Hauptstr. 7, D-79104 Freiburg .
BACKGROUND: Birch bark contains a variety of apoptosis-inducing and anti-inflammatory substances such as betulinic acid, betulin, oleanolic acid and lupeol. Therefore, birch bark extract may be effective in the treatment of actinic keratoses. To address this issue, a pilot study using a standardized birch bark ointment was performed. METHODS: Twenty-eight patients with actinic keratoses were enrolled in this prospective, non-randomized pilot study. Fourteen patients were treated with birch bark ointment only; fourteen patients received a combination therapy with cryotherapy and birch bark ointment. Treatment response was assessed clinically after two months. RESULTS: Clearing of more than 75 % of the lesions was seen in 79 % of the patients treated with birch bark ointment monotherapy. The response rate of the combined treatment modality was 93 %. Therapy with birch bark ointment was well tolerated. CONCLUSION: In this pilot study, a standardized birch bark extract was effective in the treatment of actinic keratoses. This therapy is easy to perform and it has no side effects. Birch bark ointment may be a new therapeutic option for actinic keratoses.
PMID: 16503940 [PubMed - indexed for MEDLINE

Betulinic acid derivatives as anticancer agents: structure activity relationship.

•  Mukherjee R ,
•  Kumar V ,
•  Agarwal SK ,
•  Burman AC .
Medicinal Chemistry, Dabur Research Foundation, 22 Site IV, Sahibabad, Ghaziabad 201010, UP, India .
Betulinic acid, a pentacyclic triterpene, is widely distributed throughout the tropics. It possesses several biological properties such as anticancer, anti-inflammatory, antiviral, antiseptic, antimalarial, spermicidal, antimicrobial, antileshmanial, antihelmentic and antifeedent activities. However, betulinic acid was highly regarded for its anticancer and anti-HIV activities. Anticancer role of betulinic acid appeared by inducing apoptosis in cells irrespective of their p53 status. Due to high order safety in betulinic acid, a number of structural modifications carried out to improve its potency and efficacy. The C-1, C-2, C-3, C-4, C-20 and C-28 positions are the diversity centers in betulinic acid, and the derivatives resulted on various structural modifications at these positions screened for their anticancer activity. This review presents the structure activity relationship carried out on C-1, C-2, C-3, C-4, C-20, C-28, A-ring, D-ring and E-ring modified betulinic acid derivatives. We have compiled the most active betulinic acid derivatives along with their activity profile in each series. Structure activity relationship studies revealed that C-28 carboxylic acid was essential for the cytotoxicity. The halo substituent at C-2 position in betulinic acid enhanced the cytotoxicity. Though the relation of the cytotoxicity with the nature of substituents at C-3 position could not be generalized but the ester functionality appeared to be a better substituent for enhancing the cytotoxicity. An interesting observation is that the three rings skeleton (A, B and C rings) had played an important role in eliciting anticancer activity, which could be a new molecular skeleton to design new anticancer drugs.
PMID: 16712455 [PubMed - indexed for MEDLINE]

[iii] Honda T, Liby KT, Su X, Sundararajan C, Honda Y, Suh N, Risingsong R, Williams CR, Royce DB, Sporn MB, Gribble GW. Related Articles, Links Design, synthesis, and anti-inflammatory activity both in vitro and in vivo of new betulinic acid analogues having an enone functionality in ring A. 
Bioorg Med Chem Lett. 2006 Dec 15;16(24):6306-9. Epub 2006 Sep 25. 
PMID: 16996735 [PubMed - in process]

[iv] Cancer Lett. 2006 Dec 12; [Epub ahead of print] Links

Broad in vitro efficacy of plant-derived betulinic acid against cell lines derived from the most prevalent human cancer types.

•  Kessler JH ,
•  Mullauer FB ,
•  de Roo GM ,
•  Medema JP .
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, Academic Medical Center (AMC), Meibergdreef 9, 1105 AZ Amsterdam , The Netherlands .
Betulinic acid (BA) is a widely available plant-derived triterpene with reported activity against cancer cells of neuroectodermal origin and leukaemias . Treatment with BA was shown to protect mice against transplanted human melanoma and led to tumor regression. In contrast, cells from healthy tissues were resistant to BA and toxic side-effects in animals were absent. These findings have raised interest in the chemotherapeutical anti-cancer potential of BA. A comprehensive assessment of the efficacy of BA against the clinically most important cancer types is currently lacking. Therefore, we tested the in vitro sensitivity of broad cell line panels derived from lung, colorectal, breast, prostate and cervical cancer, which are the prevalent cancer types characterized with highest mortalities in woman and men. Multiple assays were used in order to allow a reliable assessment of anti-cancer efficacy of BA. After 48h of treatment with BA, cell viability as assessed with MTT and cell death as measured with propidium iodide exclusion showed clear differences in sensitivity between cell lines. However, in all cell lines tested colony formation was completely halted at remarkably equal BA concentrations that are likely attainable in vivo. Our results substantiate the possible application of BA as a chemotherapeutic agent for the most prevalent human cancer types.
PMID: 17169485 [PubMed - as supplied by publisher]

[v] Int J Cancer. 2006 Jan 1;118(1):246-52. Click here to read  Links

Betulinic acid, a natural cytotoxic agent, fails to trigger apoptosis in human Burkitt's lymphoma-derived B-cell lines.

•  Karpova MB ,
•  Sanmun D ,
•  Henter JI ,
•  Smirnov AF ,
•  Fadeel B .
Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska University Hospital , Stockholm , Sweden .
Betulinic acid (BA), a pentacyclic triterpene of natural origin, effectively induces apoptosis in neuroectodermal tumors and was recently shown to be a potent trigger of cell death in human leukemia-derived cell lines. To explore the potential of BA in the treatment of hematologic malignancies, we tested a panel of 10 Burkitt's lymphoma (BL)-derived B-cell lines for sensitivity to BA. The human Jurkat T leukemia cell line was included as a positive control. Our studies show that BA exerts cytotoxic effects in some of the BL cell lines tested, including DG75, a chemoresistant BL cell line. However, cell death was caspase-independent, as evidenced by a lack of protection by zVAD-fmk, a pancaspase inhibitor, and displayed signs of necrosis. Furthermore, BA-induced caspase activation was seen to a minor extent in only 1 of the 10 BL cell lines tested (Ramos, a p53-deficient cell line), but was readily detected in Jurkat cells. Together, these studies indicate that resistance to BA-induced apoptosis is a common feature of BL-derived cell lines. Copyright 2005 Wiley-Liss, Inc.
PMID: 16003746 [PubMed - indexed for MEDLINE]

[vi] Eur J Pharm Sci. 2006 Sep;29(1):1-13. Epub 2006 Apr 29.   Links

Pharmacological properties of the ubiquitous natural product betulin.

•  Alakurtti S ,
•  Makela T ,
•  Koskimies S ,
Faculty of Pharmacy, Division of Pharmaceutical Chemistry, University of Helsinki , Helsinki , Finland .
Betulin (lup-20(29)-ene-3beta,28-diol) is an abundant naturally occurring triterpene and it is found predominantly in bushes and trees forming the principal extractive (up to 30% of dry weight) of the bark of birch trees . Presently, there is no significant use for this easily isolable compound, which makes it a potentially important raw material for polymers and a precursor of biologically active compounds. Betulin can be easily converted to betulinic acid, which possesses a wide spectrum of biological and pharmacological activities. Betulinic acid has antimalarial and anti-inflammatory activities. Betulinic acid and its derivatives have especially shown anti-HIV activity and cytotoxicity against a variety of tumor cell lines comparable to some clinically used drugs . A new mechanism of action has been confirmed for some of the most promising anti-HIV derivatives, which makes them potentially useful additives to the current anti-HIV therapy. Betulinic acid is specifically cytotoxic to several tumor cell lines by inducing apoptosis in cells. Moreover, it is non-toxic up to 500 mg/kg body weight in mice. The literature concerning derivatization of betulin for structure-activity relationship (SAR) studies and its pharmacological properties is reviewed.
PMID: 16716572 [PubMed - indexed for MEDLINE]

[vii] Oncol Rep. 2005 Sep;14(3):667-71. Links

Combination of betulinic acid with cisplatin--different cytotoxic effects in two head and neck cancer cell lines.

•  Czembirek C ,
•  Erovic BM ,
•  Selzer E ,
•  Turhani D ,
•  Vormittag L ,
•  Thurnher D .
Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Betulinic acid (BetA), a new experimental cytotoxic compound that is active against human melanoma cells and neuroectodermal tumor cells, has recently been shown to be also effective against head and neck squamous carcinoma cells (HNSCC). In this study we investigated BetA in combination with cisplatin in squamous cell carcinoma cell lines of the tongue. SCC25 and SCC9 were treated with BetA and/or cisplatin. Cells were counted with an automated analyzing system. Caspase activation was determined using the M30 Cyto-Death ELISA, expression of the anti-apoptotic protein Mcl-1 by Western blot analysis. Visualization of apoptotic cells was achieved by immunohistochemistry. Synergistic cytotoxic effect and the induction of apoptosis under combined treatment was observed in SCC25 cells only after 24 or 48 h, whereas treatment of SCC25 cells for 72 h with BetA and cisplatin showed antagonism or subadditive effects. In SCC9 cells, antagonism occurred over an increase of dose and time during treatment. Furthermore, we could not demonstrate a significant alteration in the expression of the anti-apoptotic protein, Mcl-1. Our in vitro data demonstrate that BetA seems to be an unlikely candidate for combination with cisplatin in the treatment of head and neck cancer.
PMID: 16077972 [PubMed - indexed for MEDLINE]

[viii] Planta Med. 2006 Nov 7; [Epub ahead of print]   Links

Physical, Chemical and Pharmacological Characterization of a New Oleogel-Forming Triterpene Extract from the Outer Bark of Birch (Betulae Cortex).

•  Laszczyk M ,
•  Jager S ,
•  Scheffler A ,
•  Schempp CM .
Carl Gustav Carus-Institut, Niefern-Oschelbronn , Germany .
Triterpenes are biologically active secondary plant substances that display antimicrobial, hepatoprotective and anti-inflammatory effects. However, the poor solubility of triterpenes in both polar and non-polar solvents as well as expensive purification procedures have prevented the large-scale isolation of these compounds for medicinal purposes. Here, we describe a novel quantitative extraction method of triterpenes from the outer bark of birch ( BETULA species) in which betulin, a lupan triterpene, predominates. The resulting highly purified triterpene extract (TE) in the form of a dry powder contains betulin as the major compound, but also betulinic acid, lupeol, erythrodiol and oleanolic acid. We have found that this TE is able to form an oleogel, thus providing an opportunity for the topical application of pharmacologically relevant amounts of triterpenes. Furthermore, we have investigated the TE in comparison to its major isolated compounds in cell culture experiments with human immortalized keratinocytes and skin cancer cells. We could demonstrate dose-dependent cytotoxic and apoptosis-inducing effects of TE and betulin. These experimental data support the notion from a previous clinical study that TE from the outer bark of birch might represent a new tool for the topical treatment of skin cancer and skin cancer precursors like actinic keratoses.
PMID: 17091432 [PubMed - as supplied by publisher]

January 31, 2006
  NATURNORTH TECHNOLOGIES BUILDING BIRCH BARK PROCESSING FACILITY NEAR DULUTH  
Duluth, MN-NaturNorth Technologies LLC (NaturNorth) has begun construction of a commercial production facility-the first of its kind- in Two Harbors, about 20 miles north of Duluth. The facility will concentrate the bark of the white paper birch tree (betula papyrifera) into material that will be further processed into large quantities of bioactive, low-toxicity compounds, like betulin and betulinic acid, potentially useful in antifungals, antibacterials, and antivirals for use in pharmaceuticals, cosmetics, crop protection and preservatives. 
The Two Harbors facility is expected to start operating in early April of 2006. It will be the first facility in the world to process birch bark into material that can be efficiently converted into commercial quantities of bioactive compounds. This also represents NaturNorth's first effort to invest in capabilities to develop commercial quantities of birch bark. “The Two Harbors bark processing facility represents a strategic move to construct a significant production facility and a demonstration site for our technology as well as lay the groundwork for further expansion as commercial opportunities develop,” said David Peterson, President and CEO of NaturNorth. “The new facility will initially employ five people,” he said. 
Peterson emphasized that NaturNorth will be getting its supply of bark from existing forest products companies, where birch bark is a by-product of their commercial operations. “Extracting betulin from birch bark and producing betulinic acid for cosmetic and medicinal purposes represent exciting potential uses for this otherwise wasted resource from Minnesota 's forest products industry.” 
NaturNorth's mission is to identify, develop and produce natural, high-purity commercial compounds from birch bark and their active derivatives. NaturNorth is able to supply commercial quantities of previously unavailable bioactive natural products and their derivatives for use in high-value applications. 
NaturNorth is a public-private partnership between the University of Minnesota Duluth, Potlatch Corporation (NYSE: PCH) and Synertec, a subsidiary of ALLETE, Inc. (NYSE: ALE). Technologies to extract the betulin were developed at UMD's Natural Resources Research Institute. “Together, these partners have guided and supported NaturNorth and we are pleased to have the opportunity to support this business in Minnesota ,” said L. Pendleton Siegel, Chairman and CEO, Potlatch Corporation.


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