A novel approach to target hypoxic cancer cells via combining ?-oxidation inhibitor etomoxir with radiation.
Hypoxia (Auckland, N.Z.)
2018; 6: 23?33
Silibinin Treatment Inhibits the Growth of Hedgehog Inhibitor-Resistant Basal Cell Carcinoma Cells via Targeting EGFR-MAPK-Akt and Hedgehog Signaling.
Photochemistry and photobiology
2017; 93 (4): 999?1007
Hypoxia in tumors is associated with resistance towards various therapies including radiotherapy. In this study, we assessed if hypoxia in cancer spheres could be effectively reduced by adding etomoxir (a ?-oxidation inhibitor) immediately after cell irradiation.We employed cancer cells' sphere model to target hypoxia. Confocal imaging was used to analyze hypoxia and expression of specific biomarkers in spheres following various treatments (radiation and/or etomoxir).Etomoxir (32.5 ?M) treatment improved the radiation (2.5 Gy) efficacy against growth of lung adenocarcinoma H460 spheres. More importantly, radiation and etomoxir combination significantly reduced the hypoxic regions (pimonidazole+ areas) in H460 spheres compared to either treatment alone. Also, etomoxir and radiation combination treatment reduced the protein level of biomarkers for proliferation (Ki-67 and cyclin D1), stemness (CD44) and ?-oxidation (CPT1A) in H460 spheres. We observed similar efficacy of etomoxir against growth of prostate cancer LNCaP cells' spheres when combined with radiation. Further, radiation treatment strongly reduced the hypoxic regions (pimonidazole+ areas) in CPT1 knockdown LNCaP cells' spheres.Together, these results offer a unique approach to target hypoxia in solid tumors via combining etomoxir with radiation, thereby improving therapeutic efficacy.
View details for DOI 10.2147/HP.S163115
View details for PubMedID 30175155
View details for PubMedCentralID PMC6109663
Basal cell carcinoma (BCC) is the most common skin malignancy. Deregulated hedgehog signaling plays a central role in BCC development; therefore, hedgehog inhibitors have been approved to treat locally advanced or metastatic BCC. However, the development of resistance to hedgehog inhibitors is the major challenge in effective treatment of this disease. Herein, we evaluated the efficacy of a natural agent silibinin to overcome resistance with hedgehog inhibitors (Sant-1 and GDC-0449) in BCC cells. Silibinin (25-100 ?m) treatment for 48 h strongly inhibited growth and induced death in ASZ001, Sant-1-resistant (ASZ001-Sant-1) and GDC-0449-resistant (ASZ001-GDC-0449) BCC cells. Furthermore, colony-forming ability of ASZ001, ASZ001-Sant-1 and ASZ001-GDC-0449 cells was completely inhibited by silibinin treatment. Molecular analysis showed that silibinin treatment decreased the level of phosphorylated EGFR (Tyrosine 1173) and total EGFR in ASZ001-Sant-1 cells, key signaling molecules responsible for BCC resistance toward hedgehog inhibitors. Further, silibinin treatment decreased the phosphorylated Akt (Serine 473), phosphorylated ERK1/2 (Threonine 202/Tyrosine 204), cyclin D1 and Gli-1 level but increased the SUFU expression in ASZ001-Sant-1-resistant cells. Silibinin treatment of ASZ001-Sant-1-resistant cells also decreased bcl-2 but increased cleaved caspase 3 and PARP cleavage, suggesting induction of apoptosis. Together, these results support silibinin use to target hedgehog inhibitor-resistant BCC cells.
View details for DOI 10.1111/php.12727
View details for PubMedID 28120452
View details for PubMedCentralID PMC5500419