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

Figures & data

Figure 1. Downstream molecular events after addition of LB100 to chemotherapy and radiation. The schematic diagram summarizes the major downstream molecular events that occur after LB100 is administered concurrently with chemotherapy and/or radiation. Increased and decreased expression of the target proteins is indicated by a green and red arrow, respectively. The end consequences of LB100 treatment include increased tumor permeability to drug exposure, induction of cell differentiation, and tumor cell death resulting from mitotic catastrophe or apoptosis.

Table 1. Summary of pre-clinical studies utilizing LB100. Studies reflect a review of the literature as of November 2014

Authors	Tumor Type	IC50 in vitro or Dose Enhancement Factor (DEF) in vitro	Adjuvant Therapy	Significant findings in addition to chemo/radio-sensiziation by LB100
Lu et al., 2009^70; 2010^69	Glioblastoma	IC50 = 5 μM	Temozolomide	LB100 disrupted formation of N-CoR complex, inducing cellular differentiation.Efficacy of LB100 was independent of p53 mutation status.
Zhang et al., 2010^82	Sarcoma	IC50 = 4.36 μM	Doxorubicin	LB100 effectively chemosensitized a stem cell-derived cell line.Adjuvant LB100 treatment prevented development of metastases in in vivo experiments.
Martiniova et al., 2011^90	Pheochromocytoma	IC50 = >20 μM	Temozolomide	Addition of LB100 to TMZ in vivo completely inhibited tumor formation in majority of animals.
Xu et al., 2013^103	Breast Cancer	not reported	Recombinant TRAIL	Inhibition of PP2A with LB100 overcame TRAIL-mediated resistance to apoptosis in breast cancer cells.
Lv et al., 2014^112	Nasopharyngeal Carcinoma	DEF = 1.83–1.97	Radiation	LB100 radio-sensitized known radioresistant NPC cells, in vitro and in vivo.LB100 was effective using single high dose radiation without significant treatment-related toxicity.
Bai et al., 2014^118	Hepatocellluar Carcinoma	IC50 = >10 μM	Doxorubicin	Chemosensitization by LB100 was equally effective in p53-null versus p53 intact cells.LB100 increased VEGF secretion, promoting tumor angiogenesis and drug penetration into tumor parenchyma, in vitro.
Wei et al., 2013^136 Bai et al., 2014^123	Pancreatic Cancer	DEF = 1.2–1.4; IC50 = 3.98 and 0.85	Radiation; Doxorubicin	Therapeutic LB100 and radiation doses did not harm peri-pancreatic normal duodenal cells in vitro.Radio-sensitization by LB100 was associated with inhibition of HRR pathway response to DNA damage, in vitro.LB100 promoted penetration of doxorubicin into tumor parenchyma, in vivo.
Chang et al., 2014^146	Ovarian Cancer	IC50 = 5 – 10.1 μM	Cisplatin	LB100 sensitized known cisplatin-resistant ovarian cancer cells to cisplatin treatment, in vitro and in vivo.LB100 was not subjected to drug efflux by ABC transporters, in vitro.

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