Necroptosis is a programmed form of necrosis characterized by mitochondrial alterations and plasma membrane permeabilization resulting in the release of cytoplasmic content into extracellular space, and leading to inflammatory reactions. Besides its critical role in viral defense mechanisms and inflammatory diseases, necroptosis plays pivotal functions in the drug response of tumors, including prostate cancer. Necroptosis is mainly governed by kinase enzymes, including RIP1, RIP3, and MLKL, and conversely to apoptosis, is a caspase-independent mechanism of cell death. Numerous compounds induce necroptosis in prostate cancer models, including (i) compounds of natural origin, (ii) synthetic and semisynthetic small molecules, and (iii) selenium and selenium-based nanoparticles.
Characteristic | Necroptosis | Necrosis | Apoptosis | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Involved proteins | RIP3 | + | / | / | ||||||||||
MLKL | + | / | / | |||||||||||
Caspase 3 | / | / | + | |||||||||||
Cell properties | Membrane perforation | + | + | / | ||||||||||
Membrane blebbing | / | / | + | |||||||||||
DNA fragmentation | + | + | + | |||||||||||
Cell lysis and swelling | + | + | / | |||||||||||
Inflammation | + | + | / |
Compound | NCT Number | Markers | Phase | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Curcumin | NCT03769766 | PSA | III | ||||||||
NCT03211104 | PSA | na | |||||||||
NCT02064673 | PSA | III | |||||||||
Curcumin and piperine | NCT04731844 | nd | II | ||||||||
Curcumin and ursolic acid | NCT04403568 | p65, NF-kB | I | ||||||||
Curcumin and Vitamin D, omega 3, turmeric | NCT03290417 | PSA | na | ||||||||
Curcumin and taxotere | NCT02095717 | PSA | III | ||||||||
Curcumin and radiotherapy | NCT01917890 | TNF-α, NF-kB | na | ||||||||
NCT02724618 | PSA | II | |||||||||
NCT03493997 | nd | II | |||||||||
Polyphenon E | NCT00596011 | PSA | II | ||||||||
NCT00676780 | PSA, VEGF, HGF | II | |||||||||
NCT01340599 | PSA, Ki67, Bcl2, Cyclin D, p27, VEGF, CD31, MMP2 and 9, IGF1 | II | |||||||||
NCT00459407 | MMP2, MMP9, IGF1 | I | |||||||||
NCT00253643 | FASN, Ki67 | na | |||||||||
NCT04597359 | PSA, Ki67 | II | |||||||||
BI2536 | NCT00706498 | PSA | II | ||||||||
Sorafenib | NCT00090545 | PSA | II | ||||||||
NCT00694291 | PSA | II | |||||||||
NCT00466752 | PSA, p-ERK, p-AKT, p-S6-kinase, caspase 3, Ki67 | I | |||||||||
NCT00093457 | PSA | II | |||||||||
Sorafenib and leuprolide or bicalutamide | NCT00924807 | PSA | I-II | ||||||||
Sorafenib and docetaxel | NCT00589420 | PSA | II | ||||||||
NCT00619996 | PSA, p-ERK, VEGF-R2 | II | |||||||||
Sorafenib and taxotere | NCT00405210 | PSA | I | ||||||||
Sorafenib and mitoxantrone | NCT00452387 | PSA | II | ||||||||
Sorafenib and gleevec | NCT00424385 | PSA | I | ||||||||
Selenite and docetaxel | NCT01155791 | PSA | I | ||||||||
Selenite and radiotherapy | NCT02184533 | PSA | I |