Thapsigargin from Thapsia garganica programmed to attack cancer cells

Phytochemicals from herbs, fruits and vegetables have been the source of multiple active molecules used in medicines by the medical and pharmaceutical industry under fancy and very suggestive commercial names. The medical industry realized many years ago that what it would take them ages to find nature had already found it. Think for example about how long did nature took to discover propolis, a natural antibiotic and antibacterial product with which bees sealed the beehive to protect it from external bacterial infections managing to keep beehives sterile and clean.

Or how for example, some Ginkgo biloba trees managed to survive more than 2500 years!, or for example Apigenin, a natural flavonoid found in many herbs and fruits, as Chamomile (Anthemis nobilis) used primarily in research as a protein kinase inhibitor that may suppress tumor promotion and that has anti-proliferating effects, or epigallocatechin gallate (from green tea leaves), delphinidin (a primary plant pigment responsible for the red grape color) and genistein (an isoflavone from soybeans) all associated with a lower incidence and risk of cancer [15], all that without even mention Resveratrol from red wine, able to stop breast cancer cell growth in mouse and has cardioprotective, neuroprotective and a natural anti-aging properties [16], and these are only a few examples.

THAPSIA GARGANICA

Family: Apiaceae
Genus: Thapsia
Common name: Deadly carrot.

Last year one of these companies, the company Genspera, discovered another active constituent, a phytochemical, whose name is Thapsigargin, after extracting it from a poisonous umbelliferous [1] plant called Thapsia garganica, responsible for the death of livestock by ingestion in North Africa [9], but maybe the future cure for some types of cancer and the "Cancer Achilles' heel" scientists from around the world were looking for. Want to know more?

WHAT IS THAPSIGARGIN?

Thapsigargin, with a molecular weight of 650 [12], is a sesquiterpene lactone, a naturally occurring phytochemical among the many other active constituents found in Thapsia garganica [2].

HOW DOES THAPSIGARGIN WORK?

Thapsigargin functions as a "sarco-endoplasmic reticulum calcium-ATPase (SERCA) inhibitor". But what does this mean? Well, it means Thapsigargin interferes with the intracellular calcium homeostasis process, an essential process for cell survival by which the control the uptake and release of calcium in the cytoplasm of the cell is regulated.

This blockage of this release of calcium from the cells cytoplasm a rapid elevation of intracellular calcium, this sustained rise in intracellular calcium, is the initial step for cell death [4]. This, which in principal seems to be a very effective way to fight cancer cells had one single problem, Thapsigargin does that to "all cells" without distinction. Thapsigargin didn't have a way yet to distinguish which way cancer cells look like. This was the task of GenSpera's scientists, find a characteristic on cancer cells that will serve Thapsigargin to identify them and target them. 

After investigating different cancer cell lines, GenSpera's investigators found a distinctive piece of code, a cancer cell uniform, that could be used by Thapsigargin to identify  and target only cancer cells, a peptide with 5 amino-acids. The levels achieved by Thapsigargin are extraordinary, however, other scientists are also following the example and got also good results using other molecules. German scientist from the Alfred-Wegener-Institut für Polar- und Meeresforschung, discovered another sesquiterpene, this time a sesquiterpene-hydroquinone, that was isolated from the Caribbean coral reef bioerding sponge Siphonodictyon coralliphagum, the Siphonodictyal B1, with apparently similar effects as Thapsigargin. In spite Siphonodictyal B1 has no structural similarities to Thapsigargin, they both attack cells the same way [3].

OTHER ACTIVE CONSTITUENTS FOUND IN THAPSIA GARGANICA

Other active constituents isolated from Thapsia garganica, the basiliolides, a novel class of C19 dilactones, induced a rapid mobilization of intracellular Calcium in the leukemia T-cell line Jurkat, however in contrast to thapsigargin, it did not induce apoptosis (natural cell death)[6]. Tetracyclic C-19 dilactones from the same plant also showed SERCA-inhibiting properties [8].

COOPERATION WITH THE UNIVERSITY OF COPENHAGEN

In a press release, Craig Dionne, PhD, GenSpera President and CEO, announced the agreement with the University of Copenhagen for the production of Thapsigargin, the active ingredient in GenSpera’s oncology platform. Their G-202 anti-cancer drug is in Phase I trial at three medical centers for patients whose cancer returned after other treatments failed. Genspera Inc. is also developing another drug for prostate cancer, the G-115, also derivate from thapsigargin.

Søren Brøgger Christensen, PhD, Professor at the University of Copenhagen, a member of GenSpera’s Scientific Advisory Board and the scientist responsible for the initial isolation and characterization of thapsigargin also announced:

"The Danish Council for Strategic Research has recognized the potential of developing sustainable protocols for producing valuable natural products and agrees that thapsigargin is a relevant model compound.”

GenSpera's G-115 and G-301 drugs are directly targeting prostate cancer.

REFERENCES

[1] Year-book of pharmacy

[2] Wikipedia (http://en.wikipedia.org/wiki/Thapsigargin)

[3] Siphonodictyal B1 from a marine sponge increases intracellular calcium levelscomparable to the Ca2+-ATPase (SERCA) inhibitor thapsigargin.Bickmeyer U, Grube A, Klings KW, Pawlik JR, Köck M. Alfred-Wegener-Institut für Polar- und Meeresforschung in der Helmholtz-Gemeinschaft, Biologische Anstalt Helgoland, Kurpromenade 201, 27498 Helgoland, Germany.

[4] Inhibitor of sarco-endoplasmic reticulum Ca2+-ATPase thapsigargin stimulates production of nitric oxide and secretion of interferon-gamma. Kmonícková E, Melkusová P, Harmatha J, Vokác K, Farghali H, Zídek Z. Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 
Department of Pharmacology, v.v.i., Vídenská 1083, 142 20 Prague 4, Czech Republic.

[5] Cytotoxic phenylpropanoids and an additional thapsigargin analogue isolated from Thapsia garganica. Liu H, Jensen KG, Tran LM, Chen M, Zhai L, Olsen CE, Søhoel H, Denmeade SR, Isaacs JT, Christensen SB. Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.

[6] Basiliolides, a class of tetracyclic C19 dilactones from Thapsia garganica, release Ca(2+) from the endoplasmic reticulum and regulate the activity of the transcription factors nuclear factor of activated T cells, nuclear factor-kappaB, and activator protein 1 in T lymphocytes. Navarrete C, Sancho R, Caballero FJ, Pollastro F, Fiebich BL, Sterner O, Appendino G, Muñoz E. Departamento de Biología Celular, Fisiología e Inmunología, Facultad de Medicina, Avda. 
de Menéndez Pidal s/n, Universidad de Córdoba, 14004 Córdoba, Spain.

[7] New strategies for the medical treatment of prostate cancer. Isaacs JT. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orlerans Street, CRB 1M44, Baltimore, MD 21231-1001, USA.

[8] SERCA-inhibiting activity of C-19 terpenolides from Thapsia garganica and their possible biogenesis. Appendino G, Prosperini S, Valdivia C, Ballero M, Colombano G, Billington RA, Genazzani AA, Sterner O. Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Viale Ferrucci 33, 28100 Novara, Italy.

[9] Thapsia garganica L: a poisonous plant of North Africa. El Bahri L, Makhlouf M. Service de Pharmacie-Toxicologie, Ecole Nationale de Medecine Veterinaire, Sidi-Thabet, Tunisia.

[10] Synergism between thapsigargin and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate on the release of [14C]arachidonic acid and histamine from rat peritoneal mast cells. Jacobsen S, Hansen HS, Jensen B.

[11] Effects of the sesquiterpene lactone tetraesters thapsigargicin and thapsigargin, from roots of Thapsia garganica L., on isolated spinach chloroplasts. Santarius KA, Falsone G, Haddad H.

[12] On the mechanism of histamine release induced by thapsigargin from Thapsia garganica L. Patkar SA, Rasmussen U, Diamant B.

[13] Bulletin of the history of medicine, Volume 40

[14] GenSpera Update Report issued November 21, 2011 on http://www.genspera.com/press/pr_112806.pdf

[15] Anticancer properties of flavonoids: roles in various stages of carcinogenesis. Clere N, Faure S, Martinez MC, Andriantsitohaina R. INSERM UMR U694, Université d'Angers, Angers, France.

[16] Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model.Schlachterman A, Valle F, Wall KM, Azios NG, Castillo L, Morell L, Washington AV, Cubano LA, Dharmawardhane SF. Department of Anatomy and Cell Biology, Universidad Central del Caribe School of Medicine, Bayamon, PR 00960, USA.