Article Figures & Data
Figures
- Figure 1
PP2A holoenzyme. (A) Schematic representation of the PP2A holoenzyme, which consists of 3 subunits: a core dimer scaffold A subunit, a regulatory B subunit, and a catalytic C subunit. The scaffold A and catalytic C subunits are encoded by 2 distinct genes, α and β. The regulatory B subunits are classified into 4 unrelated families, each encoded by multiple genes: B (PR55), B′ (PR56/61), B″ (PR48/59/72/130), and B’″ (PR93/110 or striatin). Genetic information was obtained from the UniProt protein sequence database [https://www.uniprot.org/ (accessed on May 1 2022)]. (B) Crystal structure of PP2A bound to PP2A phosphatase activator and ATPγS (PDB 4LAC)10, with PP2A-A depicted in orange, PP2A-B depicted in green, and PP2A-C depicted in purple. (C) Crystal structure of PP5 bound to LB100, showing LB100 coordinating with metal ions and key residues at the PP5 catalytic site (PDB 5WG8)11. PP2A-C and PP5-C share a common catalytic mechanism11. Thus, the interaction between PPP5 and LB100 may provide insight into the interaction between PP2A and LB100.
- Figure 2
Downstream molecular events after LB100 adjuvant therapy. The schematic diagram summarizes the major downstream molecular events occurring after LB100 is administered concurrently with chemotherapy, radiation, and/or immunotherapy. Increased or decreased expression of the target proteins is indicated by a red or green arrow, respectively. The major effects of LB100 include activating the host immune system, targeting cancer stem cells through canonical signaling pathways, triggering mitotic catastrophe, and promoting tumor cell death through apoptosis.
Tables
- Table 1
Overview of reviewed preclinical studies on LB100. Studies reflect a review of the literature as of May 1, 2022.
Investigators (year) Tumor type Treatment method Outcome Cui et al.21 (2020) Glioblastoma LB100 and CAR-T cell therapy Anti-CAIX CAR-T cell therapy and LB100 combination therapy significantly increased tumor-infiltrating lymphocytes (P < 0.05) and prolonged survival (P < 0.001) in xenograft U251-Luc GBM mice. Maggio et al.22 (2020) Glioblastoma LB100 and PD-1 inhibition Combination therapy, compared with monotherapy, significantly increased survival of syngeneic GL261-Luc GBM mice (P < 0.05). Complete tumor regression occurred in 25% of combination-treated mice but was not observed in other treatment or control groups. Mirzapoiazova et al.23 (2022) Small-cell lung cancer LB100, carboplatin, atezolizumab, and PD-L1 inhibition LB100 and carboplatin combination treatment resulted in significantly smaller tumor size in xenograft SCLC mice than controls (P < 0.001). LB100 administration also increased carboplatin uptake in tumor cells (P < 0.001). Triple therapy with LB100, the PD-1 inhibitor atezolizumab, and anti-PD-L1 starkly destroyed H446 SCLC tumor cell spheroids, increased infiltration by activated T cells, and increased tumor cell death in vitro. Uddin et al.24 (2020) Triple-negative breast cancer LB100 only LB100 monotherapy significantly decreased tumor volume in mice bearing MB468 TNBC xenografts. Yen et al.25 (2021) Colorectal cancer, adenocarcinoma, triple-negative breast cancer, and pancreatic cancer LB100 and PD-1 inhibition LB100 and anti-PD-1 co-treatment in multiple cancerous syngeneic mouse models resulted in MLH1 protein loss, greater microsatellite instability, and significantly smaller tumor volumes than those in control groups (P = 0.01), corresponding to increased tumor neoantigen expression. Zhang et al.26 (2015) Osteosarcoma LB100 and cisplatin Combination therapy, compared with cisplatin or LB100 alone, resulted in significantly smaller tumor volumes in mice bearing 143B OS xenografts (P < 0.05). Pulmonary metastases were observed in only 20% of combination-treated mice, compared with 80% of mice treated with cisplatin alone mice and 100% of mice treated with LB100 alone. Liu et al.27 (2018) Mucoepidermoid carcinoma LB100 and cisplatin Co-treatment of MEC cells with LB100 and cisplatin decreased PP2A activity to 84.98% of control levels in vitro. Combination-treated xenograft UM-HMC1 MEC mice also exhibited a significantly smaller tumor volume than did mice treated with either drug alone. Song et al.28 (2021) Esophageal squamous cell carcinoma LB100 and paclitaxel LB100 administration attenuated PP2A expression and decreased MCL1 protein levels (P < 0.001) in paclitaxel-resistant ESCC in vitro. In vivo, mouse models of DR150 paclitaxel-resistant ESCC were treated with LB100 monotherapy and showed significant inhibition of tumor growth (P < 0.05). Hu et al.29 (2017) Acute myelogenous leukemia LB100 and daunorubicin LB100 monotherapy increased the proportion of patient-derived AML cells in G2/M phase from 13.4% to 31.5% in vitro. LB100 and daunorubicin combination therapy significantly increased cytolysis in these cell lines in vitro (P < 0.01). Lai et al.30 (2018) Chronic myelogenous leukemia LB100 and dasatinib Combination therapy resulted in significantly fewer BCR-ABL transcripts in transgenic CML mice than controls (P < 0.01). The combination also yielded a survival benefit over dasatinib monotherapy (P = 0.018) and vehicle (P = 0.001). Ho et al.31 (2018) Meningioma LB100 and radiation LB100 and concomitant radiation induced cell death by mitotic catastrophe in vitro. Mice bearing malignant IOMM-LEE meningioma xenografts demonstrated a survival benefit when treated with combination therapy compared with either monotherapy (P < 0.05). Hao et al.32 (2018) Chordoma LB100 and radiation Co-treatment increased the proportion of cells arrested in G2/M phase of the cell cycle in vitro. Tumor size was significantly smaller in xenograft U-CH1 chordoma mice treated with combination therapy than in mice in the control (P = 0.028), LB100 alone (P = 0.0014), or radiation alone (P = 0.0273) groups.
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