Sorafenib

Sorafenib (Bay 43-9006) is a potent oral active multikinase inhibitor. Sorafenib blocks autophosphorylation and activity of receptor tyrosine kinases (VEGFR-2, VEGFR-3) and RAF family kinases, thereby suppressing the RAF/MEK/ERK and PI3K/Akt pathways, inhibiting STAT3 phosphorylation, and selectively inhibiting the MAPK pathway in cancer cells. Sorafenib induces cell cycle arrest, autophagy, apoptosis, and PARP cleavage, reduces Bcl-2, Bcl-XL, cyclin D1 levels, and activates Bak and Bax. Sorafenib inhibits tumor growth and metastasis in mouse and rat models. Sorafenib can be used for cancer research, such as colon, breast, non-small-cell lung cancer (NSCLC), ovarian, pancreatic, melanoma, colorectal and hepatocellular carcinoma^{[1][2][3][4][5][6]}. IC50 & Target:IC50: 6 nM (Raf-1), 20 nM (VEGFR-3), 22 nM (BRAF), 57 nM (PDGFR-β), 58 nM (Flt3), 68 nM (c-KIT), 90 nM (VEGFR-2)^[1] In Vitro:Sorafenib (0.01-3 μM; 2 h) selectively inhibits the MAPK pathway, while has no effect on the PKB pathway in MDA-MB-231 cells^[1].
Sorafenib (0.01-15 μM; 2 h) inhibits MEK 1/2 and ERK 1/2 phosphorylation in MDA-MB-231 human breast carcinoma cells (IC₅₀s of 40 and 90 nmol/L, respectively), ERK 1/2 phosphorylation in BxPC-3, LOX, HCT 116, HT-29, Colo-205, and Mia PaCa-2 cells, but does not inhibit ERK 1/2 phosphorylation in A549 and NCI-H460 cells^[1].
Sorafenib (0.01-10 μM; 72 h) inhibits proliferation of MDA-MB-231 cells with an IC₅₀ of 2600 nmol/L)^[1].
Sorafenib (8.9 μM) exhibits an IC₅₀ of 8.9 μM in human colorectal carcinoma HCT8 and HT29 cell lines, and causes marked antagonism with oxaliplatin and cisplatin across all tested incubation schedules, reducing platinum-induced cytotoxicity^[2].
Sorafenib (4-24 μM; 24 h) reduces expression of p21^Cip1 protein and cyclin D1 expression in HCT8 and HT29 cells when incubated simultaneously with Oxaliplatin (HY-17371) or Cisplatin (HY-17394)^[2].
Sorafenib (24 μM; 4 h) significantly reduces Cisplatin- and Oxaliplatin-induced DNA adduct levels in HCT8 and HT29 cells when applied simultaneously, but does not affect adduct levels or repair when applied consecutively^[2].
Sorafenib (0-20 μmol/L; 24-72 h) inhibits the proliferation of HCCLM3, HepG2, and rat Morris hepatoma 3924A (MH) HCC cell lines in a time- and dose-dependent manner^[3].
Sorafenib (0-20 μmol/L; 2-24 h) durably inhibits phosphorylation of STAT3^Y705 and ^S727, ERK1/2, and Akt, and reduces cyclin D1 expression, without altering JAK2 or SHP2 phosphorylation, in HCCLM3, HepG2, and MH HCC cell lines^[3].
Sorafenib (5 μM; 48 h) significantly increases clonogenicity, enhances tumoursphere formation, and upregulates cancer stem cell-associated pluripotency markers Sox2 and Oct4 in A549, NCI-H460, and NCI-H1299 NSCLC cells^[5].
Sorafenib (5 μM; 48 h) increases ALDH-positive cancer stem cell populations in A549 NSCLC cells^[5].
Sorafenib (5 μM; 48 h) significantly enhances migration capacity in NCI-H460 NSCLC cells^[5].
Sorafenib (5 μM; 48 h) induces epithelial-to-mesenchymal transition in NCI-H460 NSCLC cells via downregulation of E-cadherin and upregulation of N-cadherin, vimentin, and MMP2, and activates the AKT pathway via increased AKT phosphorylation^[5].
Sorafenib (5 μM; 48 h) upregulates STMN1, FOXM1, and E2F1 expression at the mRNA and protein levels in NCI-H460 and NCI-H1299 NSCLC cells^[5]. In Vivo:Sorafenib (7.5-60 mg/kg; p.o.; daily for 5 or 9 days) inhibits tumor growth, suppresses RAF/MEK/ERK signaling, and reduces angiogenesis in mouse breast, colon, and NSCLC xenograft models, with no observed toxicity^[1].
Sorafenib (30 mg/kg; i.g.; once daily; once daily from day 17 to day 38) inhibits hepatocellular carcinoma tumor growth and metastasis in an orthotopic rat Morris Hepatoma (MH) model, while inducing tumor apoptosis and suppressing STAT3, Akt, and ERK phosphorylation^[3].
Sorafenib (10 mg/kg; p.o.; daily; 2 weeks) exhibits antineoplastic activity in Diethyl Nitrosamin (DENA)-induced hepatocellular carcinoma in albino rats^[4].
Sorafenib (4 mg/kg; i.p.; twice a week for 4 weeks) in combined with intratumoral siTUC338 significantly reduces tumor volume in mouse HepG2/Sor xenografts via upregulation of RASAL1^[6].