Inhibition of CD45 Phosphatase Activity Induces Cell Cycle Arrest and Apoptosis of CD45⁺ Lymphoid Tumors Ex Vivo and In Vivo

Abstract

Src-family kinases (SFK) govern cellular proliferation of bone marrow-derived cells. SFKs are regulated by the protein tyrosine phosphatase enzymatic activity of CD45. All lymphoid cells express CD45, but only proliferating cells are dependent on CD45 activity. We postulated that compound 211 (2-[(4-acetylphenyl)amino]-3-chloronaphthoquinone), a selective inhibitor of CD45 phosphatase activity, could preferentially affect actively proliferating cells but spare resting lymphoid cells. Compound 211 inhibited CD45 and induced inappropriate SFK signaling, leading to a G2/M cell cycle arrest and apoptotic cell death. CD45 cell lines were sensitive to compound 211 cytotoxicity at low micromolar LD while control CD45 cell lines and CD45 resting primary T cells were spared any toxicity. In two syngeneic tumor models in vivo, compound 211 delayed the growth of established primary tumors and reduced tumor metastasis without causing depletion of resting T cells. This work validates targeting CD45 phosphatase enzymatic activity, which may be a druggable target for cancer therapy.

Protein tyrosine phosphatase receptor type C (PTPRC or CD45)

“…PTP inhibitor XIX (PI-19) is one potential CD45 inhibitor drug used for the treatment of organ graft rejection and autoimmunity. 39 Perron et al 40 discovered 211 (2-[(4-acetylphenyl) amino]−3chloronaphthoquinone), a selective CD45 inhibitor effective in suppressing T cell responses in a delayed hypersensitivity inflammatory model in vivo with minor toxicity to the normal immune system. This agent could be used as a potential drug to prevent the dissemination of metastasis of lymphoid tumours by targeting CD45 enzymatic activity for cancer therapy.…”

“…This agent could be used as a potential drug to prevent the dissemination of metastasis of lymphoid tumours by targeting CD45 enzymatic activity for cancer therapy. 40 This approach would protect normal non-proliferating cells that express CD45 but do not depend on CD45 activity, while clearance of the inhibitor from the body enables normal cells to resume their ability to form new enzymatically active CD45 protein and activate a normal immune response when required.…”

“…This agent could be used as a potential drug to prevent the dissemination of metastasis of lymphoid tumours by targeting CD45 enzymatic activity for cancer therapy. 40 …”

Src-family Protein Tyrosine Kinases: A promising target for treating Cardiovascular Diseases

“…For instance, SFKs activated by lipopolysaccharide (LPS) could phosphorylate Toll-like receptor 4 and then dissociate MyD88 and Mal/Tirap to suppressing inflammatory responses [26]. In all lymphoid cells expressing CD45, an inhibitor of CD45 led to abnormal SFKs signaling, resulting in a G2/M cell cycles arrest and apoptotic cell death [27]. In other organizations, the total levels and the activation levels of specific SFK members were also important for regulating apoptotic activity [28].…”

Significance of nutrient media choice for the long-term cultures of leukemic T-lymphoblasts

“…Согласно данным авторов, RPMI 1640 в три раза сильнее (в сравнении с МЕМ) подавляла активность CD45 молекулы (общий лейкоцитарный антиген; тирозиновая протеинфосфатаза) на лейкозных клетках in vitro. При этом ингибиция CD45-фосфатазной активности приводит к аресту клеточного цикла и апоптозу Jurkat Т-клеток [23].…”