Thapsia Garganica is a common Mediterranean weed highly toxic to sheep and cattle, thus earning the nickname death carrot.
Thapsigargin is a natural cytotoxin derived from the plant Thapsia Graganica. Oncologists Samuel Denmeade at Johns Hopkins University, Baltimore and his team has extensively researched methods to harness thapsigargin's toxicity, and develop, as result, a potential and novel anti-cancer therapeutic and diagnostic tool. The end result is the thapsigargin analog prodrug, mipsagargin.
Thapsigargin is an irreversible inhibitor of sarcoplasmic reticulum/endoplasmic reticulum Ca++ ATPase (SERCA). SERCA pumps calcium ions from cytoplasm into the lumen of the endoplasmic reticulum (ER), and thapsigargin, by preventing this, causes an increase in the cytoplasmic calcium levels while depleting ER stores. Increased cytoplasmic calcium, in turn, activates plasma membrane calcium channels, allowing more calcium to enter into the cells. Thapsigargin also interferes with mechanisms of autophagy by inhibiting fusion of autophagosomes to lysosomes. Thus, increased calcium levels along with dysregulated autophagy leads to ER stress, which ultimately progresses to apoptosis and cell death.
So, how is this lethality harnessed and diverted towards killing the bad guys cancer cells? To prevent thapsigargin from expressing its cytotoxicity on normal cells, a peptide ligand is attached to the end of the thapsigargin molecule that renders it inactive. As long as the peptide ligand is attached to the thapsigargin analog, it is harmless.
Prostate cancer cells secrete unique proteases--prostate specific membrane antigen (PSMA) and human glandular kallikrein 2 (hK2). PSMA is only present in the vasculature of solid tumors. The peptide ligand attached to the thapsigargin analog molecule is cleaved off by PSMA, activating thapsigargin and triggering apoptosis (cell death) of the cancer cells in the process.
PSMA is a type ll membrane glycoprotein expressed by all prostate cancers. Despite its name, PSMA is also expressed in the vasculature of other solid tumors including bladder, pancreas, lung, and kidney cancers, but not in normal vasculature.
For years, PSMA has been an attractive target in developing anti-cancer diagnostic and therapeutic agents. After compelling preclinical results, mipsagargin has entered clinical trials. GenSpera, Inc. is a clinical-stage oncology drug discovery and development company. Its lead drug candidate mipsagargin is currently clinical trials are being conducted for hepatocellular carcinoma (HCC), glioblastoma multiforme (GBM), prostate cancer, and renal cell carcinoma (RCC).
Mipsagargin has completed phase 2 trials for HCC or liver cancer on patients previously treated with nexavar (sorafanib), the only treatment available for liver cancer. According to GenSpera, no serious side effects were observed except for kidney injury, of which was treated by lower dosing and increased hydration for patients during drug administration.
Recently, mipsagargin has entered phase 2 trials for GBM or brain tumors. According to preclinical research, clinically relevant concentrations of thapsigargin eliminate the glioblastoma cell reproductive capacity as a consequence of cell death.
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Janssen S, Rosen DM, Ricklis RM, Dionne CA, Lilja H, Christensen SB, Isaacs JT, Denmeade SR. Pharmacokinetics,Biodistribution, and Antitumor Efficacy of a Human Glandular Kallikrein 2(hK2)- Activated Thapsigargin Prodrug.Â Prostate. 2006;66(4):358-68.
Afshin Samali,Â Una FitzGerald,Â Shane Deegan, and Sanjeev Gupta. Methods for monitoring Endoplasmic reticulum Stress and the unfolded protein response. International Journal of Cell Biology. 2010 (2010), Article ID 830307.
Quick QA, Faison MO. CHOP and caspase 3 induction underlie glioblastoma cell death in response to endoplasmic reticulum stress. Experimental and Therapeutic Medicine. 2012;3(3):487-492. doi:10.3892/etm.2011.422.
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[Authored by Dilshad Rafi Ahmed]