A novel biguanide derivative, IM176, induces prostate cancer cell death by modulating the AMPK-mTOR and androgen receptor signaling pathways
Background: Metformin and phenformin, biguanide derivatives that are widely used to treat type 2 diabetes mellitus, have recently been shown to exert potential anticancer effects in prostate cancer. This study compared the antiprostate cancer effects of the novel biguanide derivative IM176 with thos...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Prostate International |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2287888222000666 |
| _version_ | 1797808427464916992 |
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| author | Yunlim Kim Sangjun Yoo Bumjin Lim Jun Hyuk Hong Cheol Kwak Dalsan You Jung Jin Hwang Choung-Soo Kim |
| author_facet | Yunlim Kim Sangjun Yoo Bumjin Lim Jun Hyuk Hong Cheol Kwak Dalsan You Jung Jin Hwang Choung-Soo Kim |
| author_sort | Yunlim Kim |
| collection | DOAJ |
| description | Background: Metformin and phenformin, biguanide derivatives that are widely used to treat type 2 diabetes mellitus, have recently been shown to exert potential anticancer effects in prostate cancer. This study compared the antiprostate cancer effects of the novel biguanide derivative IM176 with those of metformin and phenformin. Methods: Prostate cancer cell lines and patient-derived castration-resistant prostate cancer (CRPC) cells were treated with IMI76, metformin, and phenformin. The effects of these agents on cell viability, annexin V-FITC apoptosis, mammalian target of rapamycin inhibition, protein expression and phosphorylation, and gene expression were evaluated. Results: IM176 dose dependently reduced the viability of all prostate cancer cell lines tested, with IC50s (LNCaP: 18.5 μM; 22Rv1: 36.8 μM) lower than those of metformin and phenformin. IM176 activated AMP-activated protein kinase, inhibiting mammalian target of rapamycin and reducing the phosphorylation of p70S6K1 and S6. IM176 inhibited the expression of androgen receptor, the androgen receptor splice variant 7, and prostate-specific antigen in LNCaP and 22Rv1 cells. IM176 increased caspase-3 cleavage and annexin V-positive/propidium iodide–positive cells, which indicated apoptosis. Moreover, IM176 reduced viability, with low IC50, in cultured cells derived from two patients with CRPC. Conclusion: The antitumor effects of IM176 were comparable with those of other biguanides. IM176 may therefore be a novel candidate for the treatment of patients with prostate cancer, including those with CRPC. |
| first_indexed | 2024-03-13T06:37:20Z |
| format | Article |
| id | doaj.art-ad5d12662e0847788413e22e02e49695 |
| institution | Directory Open Access Journal |
| issn | 2287-8882 |
| language | English |
| last_indexed | 2024-03-13T06:37:20Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Prostate International |
| spelling | doaj.art-ad5d12662e0847788413e22e02e496952023-06-09T04:28:18ZengElsevierProstate International2287-88822023-06-011128390A novel biguanide derivative, IM176, induces prostate cancer cell death by modulating the AMPK-mTOR and androgen receptor signaling pathwaysYunlim Kim0Sangjun Yoo1Bumjin Lim2Jun Hyuk Hong3Cheol Kwak4Dalsan You5Jung Jin Hwang6Choung-Soo Kim7Asan Institute for Life Sciences, Asan Medical Center, Seoul, KoreaDepartment of Urology, Seoul National University, Boramae Medical Center, Seoul, KoreaDepartment of Urology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, KoreaDepartment of Urology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, KoreaDepartment of Urology, Seoul National University Hospital, Seoul, KoreaDepartment of Urology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; Corresponding author. Department of Urology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul 05505, Korea.Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea; Corresponding author. Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul 05505, Korea.Department of Urology, Ewha Womans University Mokdong Hospital, Seoul, Korea; Corresponding author. Department of Urology, Ewha Womans University Mokdong Hospital, 1071, Anyangcheon-ro, Yangcheon-gu, Seoul 07985, Korea.Background: Metformin and phenformin, biguanide derivatives that are widely used to treat type 2 diabetes mellitus, have recently been shown to exert potential anticancer effects in prostate cancer. This study compared the antiprostate cancer effects of the novel biguanide derivative IM176 with those of metformin and phenformin. Methods: Prostate cancer cell lines and patient-derived castration-resistant prostate cancer (CRPC) cells were treated with IMI76, metformin, and phenformin. The effects of these agents on cell viability, annexin V-FITC apoptosis, mammalian target of rapamycin inhibition, protein expression and phosphorylation, and gene expression were evaluated. Results: IM176 dose dependently reduced the viability of all prostate cancer cell lines tested, with IC50s (LNCaP: 18.5 μM; 22Rv1: 36.8 μM) lower than those of metformin and phenformin. IM176 activated AMP-activated protein kinase, inhibiting mammalian target of rapamycin and reducing the phosphorylation of p70S6K1 and S6. IM176 inhibited the expression of androgen receptor, the androgen receptor splice variant 7, and prostate-specific antigen in LNCaP and 22Rv1 cells. IM176 increased caspase-3 cleavage and annexin V-positive/propidium iodide–positive cells, which indicated apoptosis. Moreover, IM176 reduced viability, with low IC50, in cultured cells derived from two patients with CRPC. Conclusion: The antitumor effects of IM176 were comparable with those of other biguanides. IM176 may therefore be a novel candidate for the treatment of patients with prostate cancer, including those with CRPC.http://www.sciencedirect.com/science/article/pii/S2287888222000666Androgen receptor splice variantBiguanideCastration-resistant prostate cancerCell death |
| spellingShingle | Yunlim Kim Sangjun Yoo Bumjin Lim Jun Hyuk Hong Cheol Kwak Dalsan You Jung Jin Hwang Choung-Soo Kim A novel biguanide derivative, IM176, induces prostate cancer cell death by modulating the AMPK-mTOR and androgen receptor signaling pathways Prostate International Androgen receptor splice variant Biguanide Castration-resistant prostate cancer Cell death |
| title | A novel biguanide derivative, IM176, induces prostate cancer cell death by modulating the AMPK-mTOR and androgen receptor signaling pathways |
| title_full | A novel biguanide derivative, IM176, induces prostate cancer cell death by modulating the AMPK-mTOR and androgen receptor signaling pathways |
| title_fullStr | A novel biguanide derivative, IM176, induces prostate cancer cell death by modulating the AMPK-mTOR and androgen receptor signaling pathways |
| title_full_unstemmed | A novel biguanide derivative, IM176, induces prostate cancer cell death by modulating the AMPK-mTOR and androgen receptor signaling pathways |
| title_short | A novel biguanide derivative, IM176, induces prostate cancer cell death by modulating the AMPK-mTOR and androgen receptor signaling pathways |
| title_sort | novel biguanide derivative im176 induces prostate cancer cell death by modulating the ampk mtor and androgen receptor signaling pathways |
| topic | Androgen receptor splice variant Biguanide Castration-resistant prostate cancer Cell death |
| url | http://www.sciencedirect.com/science/article/pii/S2287888222000666 |
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