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

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

doi:10.1016/j.canlet.2018.07.004

Cited by 21 publications

(16 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another possibility is that some substrate inhibitors can interact with ABCG2 on sites other than the substrate-binding sites and cause conformational changes in the binding pocket which allosterically affect the transportation of some substrates (59). It should be noted that, although several ABCG2 inhibitors were identified as substrates through ATPase assay, overexpression of ABCG2 does not necessarily confer drug resistance to these inhibitors (49,54,(60)(61)(62). Hitherto, the detailed mechanism of this inhibitory effect remained inconclusive and desire further exploration.…”

Section: Discussionmentioning

confidence: 99%

M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells

Peng

Yang

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR.

show abstract

Section: Discussionmentioning

confidence: 99%

M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells

Peng

Yang

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…Great efforts have been made for the search of Smad3 activation inhibitors, and some compounds show good inhibitory activity against Smad3 through directly or indirectly downregulating its expression and phosphorylation, such as lingzhifuran A [12], poricoic acids [13,14], lingzhiols [15], naringenin [16], C646 [17], 25‐O‐methylalisol F [18], BT173 [19], and SIS3 (shown in Figure ) [20]. Among these compounds, SIS3 was the first specific inhibitor of Smad3 to be discovered and often used as a serviceable tool to assess the TGF‐ β /Smad3‐regulated cellular mechanisms with remarkable Smad3 inhibitory activity [21].…”

Section: Introductionmentioning

confidence: 99%

SIS3, a good candidate for the reverse of type 2 diabetes mellitus in mice

Wang

Yan

Cui

et al. 2020

Fundamemntal Clinical Pharma

View full text Add to dashboard Cite

TGF‐β signaling plays an extremely important role in the occurrence and development of type 2 diabetes mellitus (T2DM), and the blockade of TGF‐β/Smad3 pathway protests against the high‐fat diet‐induced obesity and diabetes. As a specific small molecule inhibitor of Smad3 protein, the biological activities of compound SIS3 were evaluated by high‐fat diet‐induced T2DM model mice. In vivo results indicated that SIS3 can not only significantly reduce the body weight, fat mass, and fasting blood glucose in high‐fat diet‐induced T2DM model mice, but also improve insulin sensitivity and oral glucose tolerance of high‐fat diet‐induced T2DM model mice after the injection of SIS3 with 5 mg/kg for 45 days.

show abstract

“…In addition, in LS180/MX cells, down-regulation on [ 3 H]-mitoxantrone accumulation was obviously observed after co-treatment with different concentrations of gedatolisib. Nevertheless, there is no significant alteration of Binding domains in ABC transporters, which serve as ATPase to utilize energy from ATP hydrolysis, play a key role in drug accumulation [38]. Hence, the ATPase assays were performed to detect the impact of gedatolisib on ATPase activity of both ABCB1 and ABCG2.…”

Section: Discussionmentioning

confidence: 99%

“…As a big challenge in cancer therapy, ABC transporters-, especially ABCB1-and ABCG2-mediated MDR has been widely investigated in the past 3 decades, in which period a series of reversal agents have been studied and evaluated to antagonized ABCB1-or ABCG2-mediated chemotherapeutic or target drug therapy resistance [42]. Though few of those drugs work well in clinic, screening new ABC transporter inhibitors is still remained an approach to exclude MDR [38]. Some substrate drugs also act as ABC transporter reversal agent, hence, we next evaluated the reversal capacity of gedatolisib at low toxic concentrations on ABCB1-or ABCG2-mediated MDR in CRC cells [39].…”

Section: Discussionmentioning

confidence: 99%

ABCB1 and ABCG2 restricts the efficacy of gedatolisib (PF-05212384), a PI3K inhibitor in colorectal cancer cells

Liu

Xing

et al. 2021

Cancer Cell Int

View full text Add to dashboard Cite

Background Overexpression of ABC transporters is a big challenge on cancer therapy which will lead cancer cells resistance to a series of anticancer drugs. Gedatolisib is a dual PI3K and mTOR inhibitor which is under clinical evaluation for multiple types of malignancies, including colorectal cancer. The growth inhibitory effects of gedatolisib on colorectal cancer cells have been specifically studied. However, the role of ABC transporters on gedatolisib resistance remained unclear. In present study, we illustrated the role of ABC transporters on gedatolisib resistance in colorectal cancer cells. Methods Cell viability investigations of gedatolisib on colorectal cancer cells were determined by MTT assays. The verapamil and Ko143 reversal studies were determined by MTT assays as well. ABCB1 and/or ABCG2 siRNA interference assays were conducted to verify the role of ABCB1- and ABCG2-overexpression on gedatolisib resistance. The accumulation assays of gedatolisib were conducted using tritium-labeled paclitaxel and mitoxantrone. The effects of gedatolisib on ATPase activity of ABCB1 or ABCG2 were conducted using PREDEASY ATPase Kits. The expression level of ABCB1 and ABCG2 after gedatolisib treatment were conducted by Western blotting and immunofluorescence assays. The well-docked position of gedatolisib with crystal structure of ABCB1 and ABCG2 were simulated by Autodock vina software. One-way ANOVA was used for the statistics analysis. Results Gedatolisib competitively increased the accumulation of tritium-labeled substrate-drugs in both ABCB1- and ABCG2-overexpression colorectal cancer cells. Moreover, gedatolisib significantly increased the protein expression level of ABCB1 and ABCG2 in colorectal cancer cells. In addition, gedatolisib remarkably simulated the ATPase activity of both ABCB1 and ABCG2, suggesting that gedatolisib is a substrate drug of both ABCB1 and ABCG2 transporters. Furthermore, a gedatolisib-resistance colorectal cancer cell line, SW620/GEDA, was selected by increasingly treatment with gedatolisib to SW620 cells. The SW620/GEDA cell line was proved to resistant to gedatolisib and a series of chemotherapeutic drugs, except cisplatin. The ABCB1 and ABCG2 were observed overexpression in SW620/GEDA cell line. Conclusions These findings suggest that overexpression of ABCB1 and ABCG2 may restrict the efficacy of gedatolisib in colorectal cancer cells, while co-administration with ABC transporter inhibitors may improve the potency of gedatolisib.

show abstract

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

Cited by 21 publications

References 69 publications

M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells

M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells

SIS3, a good candidate for the reverse of type 2 diabetes mellitus in mice

ABCB1 and ABCG2 restricts the efficacy of gedatolisib (PF-05212384), a PI3K inhibitor in colorectal cancer cells

Contact Info

Product

Resources

About