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10.3390/cells14211654
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

LT1-3, a Slit2-Derived Peptide, Exhibits Anti-Tumor Activity and Improves Cisplatin Therapy

by
Ting-Chien Wu
1,†,
Chen-Yi Liao
1,†,
Yu-Ying Lin
2,†,
Shu-Ming Chuang
2,
Szu-Yu Liu
2,
Chi-Hsiang Wang
2,
Shang-Er Su
1,
Siang-Wei Wu
1,
Ling-I Wang
1,
Wei-Ting Chen
1,
Sheng-Wen Cheng
1,
Yu-Tang Huang
3,
Yao-Bin Zheng
3,
Cheng-Yen Chuang
2,4,*,
Feng-Di Lung
5,* and
Jinghua Tsai Chang
1,2,6,7,*
1
Institute of Medicine, Chung Shan Medical University, 110, Sec. 1, Chien-Kuo N. Road, Taichung City 402306, Taiwan
2
Institute of Medical and Molecular Toxicology, Chung Shan Medical University, 110, Sec. 1, Chien-Kuo N. Road, Taichung City 402306, Taiwan
3
Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, 110 Sec. 1, Chien-Kuo N. Road, Taichung City 402306, Taiwan
4
Division of Thoracic Surgery, Taichung Veterans General Hospital, No. 1650, Sec. 4, Taiwan Boulevard, Taichung City 407219, Taiwan
5
Department of Chemistry, Tunghai University, Taichung, No. 1727, Sec. 4, Taiwan Boulevard, Taichung City 407224, Taiwan
6
CSMU Lung Cancer Research Center, Chung Shan Medical University, 110, Sec. 1, Chien-Kuo N. Road, Taichung City 402306, Taiwan
7
Divisions of Medical Oncology and Pulmonary Medicine, Chung Shan Medical University Hospital, 110, Sec. 1, Chien-Kuo N. Road, Taichung city 402306, Taiwan
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2025, 14(21), 1654; https://doi.org/10.3390/cells14211654
Submission received: 9 September 2025 / Revised: 2 October 2025 / Accepted: 17 October 2025 / Published: 22 October 2025
Versions Notes

Abstract

The Slit2/Robo signaling pathway acts as a tumor suppressor in various cancers. This study identified an 8-amino acid peptide, LT1-3, derived from the Slit2 LamG domain, and demonstrated its ability to inhibit lung cancer cell proliferation and invasion independently of Robo receptors. Notably, LT1-3 was non-toxic to normal cells (Beas-2B, MRC5, and HUVECs). Combination treatment of LT1-3 and cisplatin synergistically inhibited the proliferation of lung cancer cells (CL1-5, A549, H1355, H460, H23, H661), but had no inhibitory effect on H1299 and H1975. Furthermore, combination therapy prolonged the median survival of tumor-bearing immunodeficient nude mice from 27.5 days (control) to 37.5 days (LT1-3 or cisplatin) and further to 47.5 days (LT1-3/cisplatin combination). The tumor suppressor TP53 positively influences LT1-3-mediated proliferation inhibition, while MAPK8 (JNK1) and PRKACA (PKA) have been identified as negative regulators. With the exception of the p53R273 variants, most TP53 mutants retained their function in this context. The p53 reactivator APR-246 restores sensitivity of p53R273H-expressing cells to LT1-3. JNK inhibition sensitizes p53-deficient or p53R273H-expressing cells to LT1-3-mediated proliferation inhibition. LT1-3, alone or in combination with a JNK inhibitor, enhances cisplatin efficacy, even in the presence of p53 mutations. Therefore, LT1-3 possesses multifunctional antitumor properties, directly inhibiting tumor cells and enhancing the efficacy of cisplatin, without causing toxicity to normal cells. Combining LT1-3 with cisplatin holds promise as a first-line therapy for lung cancer, while LT1-3 alone may be suitable for maintenance therapy.
Keywords: LT1-3; Slit2; p53; JNK1; Cisplatin; APR246 LT1-3; Slit2; p53; JNK1; Cisplatin; APR246

Share and Cite

MDPI and ACS Style

Wu, T.-C.; Liao, C.-Y.; Lin, Y.-Y.; Chuang, S.-M.; Liu, S.-Y.; Wang, C.-H.; Su, S.-E.; Wu, S.-W.; Wang, L.-I.; Chen, W.-T.; et al. LT1-3, a Slit2-Derived Peptide, Exhibits Anti-Tumor Activity and Improves Cisplatin Therapy. Cells 2025, 14, 1654. https://doi.org/10.3390/cells14211654

AMA Style

Wu T-C, Liao C-Y, Lin Y-Y, Chuang S-M, Liu S-Y, Wang C-H, Su S-E, Wu S-W, Wang L-I, Chen W-T, et al. LT1-3, a Slit2-Derived Peptide, Exhibits Anti-Tumor Activity and Improves Cisplatin Therapy. Cells. 2025; 14(21):1654. https://doi.org/10.3390/cells14211654

Chicago/Turabian Style

Wu, Ting-Chien, Chen-Yi Liao, Yu-Ying Lin, Shu-Ming Chuang, Szu-Yu Liu, Chi-Hsiang Wang, Shang-Er Su, Siang-Wei Wu, Ling-I Wang, Wei-Ting Chen, and et al. 2025. "LT1-3, a Slit2-Derived Peptide, Exhibits Anti-Tumor Activity and Improves Cisplatin Therapy" Cells 14, no. 21: 1654. https://doi.org/10.3390/cells14211654

APA Style

Wu, T.-C., Liao, C.-Y., Lin, Y.-Y., Chuang, S.-M., Liu, S.-Y., Wang, C.-H., Su, S.-E., Wu, S.-W., Wang, L.-I., Chen, W.-T., Cheng, S.-W., Huang, Y.-T., Zheng, Y.-B., Chuang, C.-Y., Lung, F.-D., & Chang, J. T. (2025). LT1-3, a Slit2-Derived Peptide, Exhibits Anti-Tumor Activity and Improves Cisplatin Therapy. Cells, 14(21), 1654. https://doi.org/10.3390/cells14211654

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