Sunitinib, known by its chemical name SU011248, is an oral small molecular inhibitor with significant antiangiogenic and antitumor activity. It was developed to overcome the limitations of earlier tyrosine kinase inhibitors, such as SU6668 and SU5416, which had poor pharmacologic properties and limited efficacy. Sunitinib targets a range of tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), KIT, FLT3, colony-stimulating factor 1 (CSF-1), and RET. These kinases are implicated in various malignancies, making sunitinib a versatile agent in cancer therapy1.
Sunitinib's mechanism of action is multifaceted due to its ability to inhibit multiple receptor tyrosine kinases (RTKs). It inhibits angiogenesis primarily by targeting VEGFR and PDGFR, which are crucial for blood vessel formation in tumors. Additionally, sunitinib has been shown to induce apoptosis and growth arrest in renal cell carcinoma (RCC) cells by inhibiting the activity of signal transducer and activator of transcription 3 (Stat3) and reducing immunosuppressive cells within the tumor microenvironment2. Furthermore, sunitinib can modulate the function of ATP-binding cassette (ABC) transporters like P-glycoprotein (ABCB1) and ABCG2, affecting the bioavailability of coadministered drugs3.
Sunitinib has demonstrated robust antitumor activity in preclinical studies, leading to tumor regression in various cancer models. Clinically, it has shown efficacy in treating neuroendocrine, colon, and breast cancers in phase II studies. Its definitive efficacy in advanced renal cell carcinoma and imatinib-refractory gastrointestinal stromal tumors (GISTs) has led to FDA approval for these indications. Ongoing studies are investigating sunitinib's use alone or in combination with chemotherapy for various tumor types1.
Sunitinib's impact on the immune system has been noted, particularly its inhibitory effects on human peripheral T cells. This inhibition could potentially impair T-cell-mediated immune responses, which is an important consideration when using sunitinib in metastatic renal cell carcinoma patients who may also be undergoing immunotherapy5.
Sunitinib has been found to reverse drug resistance mediated by ABCG2, sensitizing cells to conventional chemotherapeutic agents. This suggests that sunitinib could be used in combination with other drugs to enhance their efficacy, particularly in cases where resistance is a significant challenge9.
While sunitinib is effective in treating RCC, it can also promote cancer progression by increasing vasculogenic mimicry and cancer stem cell phenotypes. This adverse effect is mediated through the lncRNA-ECVSR/ERβ/Hif2-α signaling pathway. Understanding this mechanism is crucial for developing strategies to counteract resistance and improve treatment outcomes6.
Sunitinib has shown potential in treating pediatric medulloblastomas by inducing apoptosis and growth arrest through the inhibition of STAT3 and AKT signaling pathways. This suggests a broader application of sunitinib beyond adult malignancies8.
In pheochromocytoma, a rare tumor type, sunitinib induces apoptosis by inhibiting the VEGFR2/Akt/mTOR/S6K1 pathways. This effect is mediated through modulation of the Bcl-2 and BAD proteins, highlighting sunitinib's potential in treating this malignancy10.
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