Details

Autor(en) / Beteiligte

• Wu, Chung-Pu
• Murakami, Megumi
• Hsiao, Sung-Han
• Liu, Te-Chun
• Yeh, Ni
• Li, Yan-Qing
• Hung, Tai-Ho
• Wu, Yu-Shan
• Ambudkar, Suresh. V.

Titel

SIS3, a specific inhibitor of Smad3 reverses ABCB1- and ABCG2-mediated multidrug resistance in cancer cell lines

Ist Teil von

• Cancer letters, 2018-10, Vol.433, p.259-272

Ort / Verlag

Ireland: Elsevier B.V

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• One of the major challenges in cancer chemotherapy is the development of multidrug resistance phenomenon attributed to the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2 in cancer cells. Therefore, re-sensitizing MDR cancer cells to chemotherapy by directly inhibiting the activity of ABC transporters has clinical relevance. Unfortunately, previous attempts of developing clinically applicable synthetic inhibitors have failed, mostly due to problems associated with toxicity and unforeseen drug-drug interactions. An alternative approach is by repositioning drugs with known pharmacological properties as modulators of ABCB1 and ABCG2. In this study, we discovered that the transport function of ABCB1 and ABCG2 is strongly inhibited by SIS3, a specific inhibitor of Smad3. More importantly, SIS3 enhances drug-induced apoptosis and resensitizes ABCB1- and ABCG2-overexpressing cancer cells to chemotherapeutic drugs at non-toxic concentrations. These findings are further supported by ATPase assays and by a docking analysis of SIS3 in the drug-binding pockets of ABCB1 and ABCG2. In summary, we revealed an additional action of SIS3 that re-sensitizes MDR cancer cells and a combination therapy with this drug and other chemotherapeutic agents may be beneficial for patients with MDR tumors. •SIS3, a specific inhibitor of Smad3, inhibits the function of ABCB1 and ABCG2.•SIS3 enhances drug-induced apoptosis in multidrug-resistant cancer cells.•SIS3 resensitizes ABCB1 and ABCG2 overexpressing cancer cells to chemotherapeutics.•ABCB1 and ABCG2 do not confer resistance to SIS3 in cancer cells.•Inclusion of SIS3 in the drug treatment may benefit patients with multidrug-resistant tumors in the future.