TY - JOUR
T1 - Mipsagargin
T2 - The beginning—not the end—of thapsigargin prodrug-based cancer therapeutics
AU - Isaacs, John T.
AU - Brennen, William Nathaniel
AU - Christensen, Søren Brøgger
AU - Denmeade, Samuel R.
N1 - Funding Information:
Acknowledgments: The authors would like to acknowledge the expert assistance of the Sidney Kimmel Comprehensive Cancer Center (SKCCC) Cell Imaging Facility, Flow Cytometry Core, Tissue Services, and Immunohistochemistry Cores supported by the SKCCC Cancer Center Support Grant P30 CA006973. We thank Marc Rosen, Alyssa Gady, Rebecca Ricklis, Laura Harris, Lizamma Antony, and Sue Dalrymple for their excellent technical assistance in performing all of the in vitro and in vivo studies.
Funding Information:
Funding: This work was supported by CaPCURE awards to J.T.I. and S.R.D., funds from David Koch to J.T.I.; Prostate Cancer Foundations (PCF) awards to J.T.I.; U.S. Department of Defense Cancer Research Program award DAMD17-00-1-0028 to SRD; Prostate P50 grant CA58236 from the NCI– Specialized Programs of Research Excellence to J.T.I.; a Rapid Access to Interventional Development (RAID) award to J.T.I.; an Aegon Scholarship in Oncology award to S.J.; Danish Cancer Society award to C.M.J.; Prostate Cancer Foundation Young Investigator Award to W.N.B.; SKCCC CCSG developmental funds P30 CA006973 to W.N.B., PCF/Movember Challenge Award to J.T.I. and S.R.D.; U.S. Department of Defense award W81XWH-13-1-0304 to J.T.I. and S.R.D.; U.S. Department of Defense Prostate Cancer Research Program award W81XWH-16-1-0410 to J.T.I.; Patrick C. Walsh Prostate Cancer Research Fund to J.T.I. and W.N.B.; the Hopkins-Allegheny Health Network Cancer Research Fund to J.T.I.; U.S. Department of Defense Prostate Cancer Research Program award W81XWH-17-1-0528 to W.N.B., and the National Cancer Institute (NCI) R01 CA255259 to W.N.B.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Søren Brøgger Christensen isolated and characterized the cell-penetrant sesquiterpene lactone Thapsigargin (TG) from the fruit Thapsia garganica. In the late 1980s/early 1990s, TG was supplied to multiple independent and collaborative groups. Using this TG, studies documented with a large variety of mammalian cell types that TG rapidly (i.e., within seconds to a minute) penetrates cells, resulting in an essentially irreversible binding and inhibiting (IC50~10 nM) of SERCA 2b calcium uptake pumps. If exposure to 50–100 nM TG is sustained for >24–48 h, prostate cancer cells undergo apoptotic death. TG-induced death requires changes in the cytoplasmic Ca2+, initiating a calmodulin/calcineurin/calpain-dependent signaling cascade that involves BAD-dependent opening of the mitochondrial permeability transition pore (MPTP); this releases cytochrome C into the cytoplasm, activating caspases and nucleases. Chemically unmodified TG has no therapeutic index and is poorly water soluble. A TG analog, in which the 8-acyl groups is replaced with the 12-aminododecanoyl group, afforded 12-ADT, retaining an EC50 for killing of <100 nM. Conjugation of 12-ADT to a series of 5–8 amino acid peptides was engineered so that they are efficiently hydrolyzed by only one of a series of proteases [e.g., KLK3 (also known as Prostate Specific Antigen); KLK2 (also known as hK2); Fibroblast Activation Protein Protease (FAP); or Folh1 (also known as Prostate Specific Membrane Antigen)]. The obtained conjugates have increased water solubility for systemic delivery in the blood and prevent cell penetrance and, thus, killing until the TG-prodrug is hydrolyzed by the targeting protease in the vicinity of the cancer cells. We summarize the preclinical validation of each of these TG-prodrugs with special attention to the PSMA TG-prodrug, Mipsagargin, which is in phase II clinical testing.
AB - Søren Brøgger Christensen isolated and characterized the cell-penetrant sesquiterpene lactone Thapsigargin (TG) from the fruit Thapsia garganica. In the late 1980s/early 1990s, TG was supplied to multiple independent and collaborative groups. Using this TG, studies documented with a large variety of mammalian cell types that TG rapidly (i.e., within seconds to a minute) penetrates cells, resulting in an essentially irreversible binding and inhibiting (IC50~10 nM) of SERCA 2b calcium uptake pumps. If exposure to 50–100 nM TG is sustained for >24–48 h, prostate cancer cells undergo apoptotic death. TG-induced death requires changes in the cytoplasmic Ca2+, initiating a calmodulin/calcineurin/calpain-dependent signaling cascade that involves BAD-dependent opening of the mitochondrial permeability transition pore (MPTP); this releases cytochrome C into the cytoplasm, activating caspases and nucleases. Chemically unmodified TG has no therapeutic index and is poorly water soluble. A TG analog, in which the 8-acyl groups is replaced with the 12-aminododecanoyl group, afforded 12-ADT, retaining an EC50 for killing of <100 nM. Conjugation of 12-ADT to a series of 5–8 amino acid peptides was engineered so that they are efficiently hydrolyzed by only one of a series of proteases [e.g., KLK3 (also known as Prostate Specific Antigen); KLK2 (also known as hK2); Fibroblast Activation Protein Protease (FAP); or Folh1 (also known as Prostate Specific Membrane Antigen)]. The obtained conjugates have increased water solubility for systemic delivery in the blood and prevent cell penetrance and, thus, killing until the TG-prodrug is hydrolyzed by the targeting protease in the vicinity of the cancer cells. We summarize the preclinical validation of each of these TG-prodrugs with special attention to the PSMA TG-prodrug, Mipsagargin, which is in phase II clinical testing.
KW - Apoptosis
KW - Calcium homeostasis
KW - Mipsagargin
KW - SERCA
KW - Targeted prodrugs
KW - Thapsia garganica
KW - Thapsigargin
KW - Tissue-specific proteases
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U2 - 10.3390/molecules26247469
DO - 10.3390/molecules26247469
M3 - Review article
C2 - 34946547
AN - SCOPUS:85121559109
SN - 1420-3049
VL - 26
JO - Molecules
JF - Molecules
IS - 24
M1 - 7469
ER -