Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms

Abstract

A variety of mechanisms maintain the integrity of the genome in the face of cell stress. Cancer cell response to chemotherapeutic and radiation-induced DNA damage is mediated by multiple defense mechanisms including polo-like kinase 1 (Plk-1), protein kinase B (Akt-1), and/or p53 pathways leading to either apoptosis or cell cycle arrest. Subsequently, a subpopulation of arrested viable cancer cells may remain and recur despite aggressive and repetitive therapy. Here, we show that modulation (activation of Akt-1 and Plk-1 and repression of p53) of these pathways simultaneously results in paradoxical enhancement of the effectiveness of cytotoxic chemotherapy. We demonstrate that a small molecule inhibitor, LB-1.2, of protein phosphatase 2A (PP2A) activates Plk-1 and Akt-1 and decreases p53 abundance in tumor cells. Combined with temozolomide (TMZ; a DNA-methylating chemotherapeutic drug), LB-1.2 causes complete regression of glioblastoma multiforme (GBM) xenografts without recurrence in 50% of animals (up to 28 weeks) and complete inhibition of growth of neuroblastoma (NB) xenografts. Treatment with either drug alone results in only short-term inhibition/regression with all xenografts resuming rapid growth. Combined with another widely used anticancer drug, Doxorubicin (DOX, a DNA intercalating agent), LB-1.2 also causes marked GBM xenograft regression, whereas DOX alone only slows growth. Inhibition of PP2A by LB-1.2 blocks cell-cycle arrest and increases progression of cell cycle in the presence of TMZ or DOX. Pharmacologic inhibition of PP2A may be a general method for enhancing the effectiveness of cancer treatments that damage DNA or disrupt components of cell replication.

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

“…Notably, patients with CNS tumors, whether primary or metastatic, have been excluded from the phase 1 trial. Aside from Lu et al who importantly showed reduced PP2A activity in normal brains of mice intraperitoneally injected with LB102, 70 further work investigating blood brain barrier penetration by LB100 or LB102 is lacking. None of the aforementioned studies utilized models of intracranial xenografted tumors, nor studied levels of LB100 in CSF after systemic treatment.…”

“…70 Although currently a standard first line therapy after surgery for patients with newly diagnosed GBM, TMZ universally fails to prevent tumor recurrence, particularly in MGMT-intact tumors. 65,71 Using U87 GBM cell lines, Lu et al demonstrated dose-dependent inhibition by LB102 of GBM cell growth (IC 50 D 5 mM).…”

Inhibition of protein phosphatase 2A with the small molecule LB100 overcomes cell cycle arrest in osteosarcoma after cisplatin treatment

“…12 Furthermore, Lu et al demonstrated that abrogation by LB100 of xenograft tumor growth, in vivo, was equally as efficacious for the alkylating agent, temozolomide, as for doxorubicin, suggesting the effects of LB100 were independent of the mechanism of action of adjuvant chemotherapy. 9 Notably, LB100 has also been shown to sensitize tumors both in vitro and in vivo to clinically relevant dosing schedules of radiation. 13,14 For osteosarcoma, adjuvant radiation has not been shown to improve overall survival after surgery and chemotherapy and therefore is not routinely offered to patients.…”

“…9,10,15 Furthermore, Lu et al demonstrated in both p53 wild type and p53 mutated glioblastoma cells that LB100 induced similar changes in Akt pathwaymediated suppression of activated p53 and induced mitotic catastrophe, suggesting the mechanism of cell death by LB100 exposure may be independent of p53 mutation status. 9 Since the adoption of adjuvant chemotherapy after surgery for the treatment of osteosarcoma, the percentage of long-term survivors in patients under age 40 has risen to 60-70%. 30 However, for those patients that present with or go on to develop metastatic disease, the prognosis remains poor, mostly due to development of drug resistance in tumors cells.…”

“…Recently, a norcantharidin-derived small molecule PP2A inhibitor, dubbed LB100 (Lixte Biotechnology Holdings, Inc.), was approved by the FDA for study in a phase I clinical trial, after having demonstrated marked chemo-and radio-sensitization of tumor cells at non-toxic doses in several tumor models. [9][10][11][12][13][14][15] When administered together with standard-of-care chemotherapy and radiation regimens, LB100 holds promising potential as a novel means of overcoming treatment resistant cancers. As such, in the present study, we evaluated the efficacy of LB100 to enhance the therapeutic effects of chemotherapy against osteosarcoma.…”