Sunitinib Reverse Multidrug Resistance in Gastric Cancer Cells by Modulating Stat3 and Inhibiting P-gp Function

Abstract

Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, has been applied in phase II clinical trial as second-line treatment for advanced gastric cancer. In this study, we determined the effect of Sunitinib on the multidrug resistance in gastric cancer cells selected by vincristine. Our results showed that Sunitinib significantly enhanced the cytotoxicity of adriamycin, vincristine, etoposide, 5-Fluorouracil, and cisplatin in multidrug-resistant gastric cancer cells (SGC7901/VCR). Sunitinib significantly increased the intracellular accumulation and retention of rhodamine 123 in the SGC7901/VCR cells. However, Sunitinib, at a concentration that reverses MDR, had no significant effect on P-gp protein or mRNA expression levels. In addition, the present study revealed that Sunitinib inhibited Stat3 and down-regulated Bcl-2 in SGC7901/VCR cells, which might also contribute to the reversal of MDR. In conclusion, Sunitinib reverses multidrug resistance in gastric cancer cells by inhibiting P-gp transporter function and modulating Stat3 and Bcl-2. Further study with Sunitinib may be helpful for developing combination therapeutic strategy or circumventing gastric cancer MDR to other conventional anti-cancer drugs.

The Lauren Classification Highlights the Role of Epithelialto- Mesenchymal Transition in Gastric Carcinogenesis: an Immunohistochemistry Study of the STAT3 and Adhesion Molecules Expression

“…In the case of gastric cancer, the involvement of STAT3 in the resistance to treatment has been reported in the literature [52][53][54][55][56]. Furthermore, this resistance is associated with the activation of Stat3 and EMT [19,57].…”

Enzyme-Transporter-Mediated Drug Interactions with Small Molecule Tyrosine Kinase Inhibitors

“…Similarly, lapatinib significantly enhanced the accumulation of doxorubicin or mitoxantrone in P‐gp or BCRP‐overexpressing cells and inhibited the transport of methotrexate and E 2 17βG by BCRP . Besides EGFR TKIs, the TKIs targeting other receptor tyrosine kinases families, such as sunitinib, crizotinib, axitinib, cabozantinib, and regorafenib, have also been found to be inhibitors of P‐gp and/or BCRP and the efflux transporter‐mediated TKI–drug interactions have been reported for several of them . For example, axitinib produced inhibition on P‐gp‐mediated transport of digoxin and BCRP‐mediated transport of topotecan, with IC50 values of 3 and 4.4 μM, respectively .…”

“…229 Besides EGFR TKIs, the TKIs targeting other receptor tyrosine kinases families, such as sunitinib, crizotinib, axitinib, cabozantinib, and regorafenib, have also been found to be inhibitors of P-gp and/or BCRP and the efflux transporter-mediated TKI-drug interactions have been reported for several of them. 46,70,221,[231][232][233][234] For example, axitinib produced inhibition on P-gp-mediated transport of digoxin and BCRP-mediated transport of topotecan, with IC50 values of 3 and 4.4 :M, respectively. 221 Crizotinib significantly increased the intracellular accumulation of rhodamine 123 and doxorubicin and inhibited the drug efflux in P-gp overexpressing cells.…”

Association of Expression Levels or Activation Status of STAT3 with Treatment Outcomes of Sunitinib in Patients with Renal Cell Carcinoma

“…Moreover, STAT3 is known to play a role in the mechanism of resistance to sunitinib in tumor cells [12].…”