Inhibition of Protein Phosphatase 2A Enhances Cytotoxicity and Accessibility of Chemotherapeutic Drugs to Hepatocellular Carcinomas

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and therapeutically challenging malignancies worldwide. For patients ineligible for "curative resection" or liver transplantation, chemotherapy is an important minimally effective option. Strategies for chemosensitization are urgently needed. Here, we report that LB-100, a serine/threonine protein phosphatase 2A (PP2A) inhibitor, enhances the cytotoxicity of chemotherapy for HCC in vitro and in vivo. We found that LB

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

“…In agreement with the study of LB100 in HCC, 119 treatment with LB100 alone in Panc-1 xenografts yielded approximately 2-fold increases in VEGF secretion compared to controls. These findings were confirmed in vitro and elevated VEGF level was accompanied by increased HIF-1a expression.…”

“…115,118 Bai et al demonstrated dose-dependent cytotoxicity in 4 different HCC cell lines after treatment with LB100 and established that doses up to 5 mM in vitro did not affect cell viability but did reduce PP2A levels to 70%. 119 As such, the authors utilized 5 mM as the treatment concentration of LB100 in conjunction with standard-of-care HCC chemotherapeutic agents, doxorubicin (0.2 mg/) and cisplatin (2 mg/mL). Inclusion of LB100 increased levels of pAkt1 in treated cell lines and also attenuated the activation of p53 in p53-intact HCC cell lines.…”

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

“…26 Doxorubicin is an alternative first-line treatment for osteosarcoma and exerts its cytotoxicity through DNA intercalation. 26 While our study only validated chemosensitization by LB100 for the single-agent, cisplatin, previous pre-clinical studies have shown enhancement of doxorubicin treatment after LB100 exposure in tumor models of glioblastoma, 27 sarcoma, 11 hepatocellular carcinoma, 15 and pancreatic cancer. 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.…”

“…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.…”

Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α

“…Currently, many strategies have been developed to enhance the effects of chemotherapy, including the use of biomaterial vectors (Kang et al, 2015), combination of synergistic small-molecule chemicals (Bai et al, 2014), nanoparticle formulation (Ni et al, 2015), etc. Apart from its direct tumor-suppressing role reported in many types of cancers (Li et al, 2010;Prasad et al, 2016), UA has also been identified as a promising natural material showing chemosensitizing effects (Nabekura, 2010;Weng et al, 2014).…”