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Danazol Mediates Collateral Sensitivity Via STAT3/Myc Related Pathway in Multidrug-Resistant Cancer Cells

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Danazol Mediates Collateral Sensitivity Via STAT3/Myc Related Pathway in Multidrug-Resistant Cancer Cells www.nature.com/scientificreports OPEN Danazol mediates collateral sensitivity via STAT3/Myc related pathway in multidrug-resistant Received: 14 May 2019 Accepted: 30 July 2019 cancer cells Published: xx xx xxxx Ying-Tzu Chang1, Yu-Ning Teng2, Kun-I Lin3,4, Charles C. N. Wang 5, Susan L. Morris-Natschke6, Kuo-Hsiung Lee6,7 & Chin-Chuan Hung1,8 Multidrug resistance presents an obstacle in cancer treatment. Among numerous combative strategies, collateral sensitivity (CS) drugs have opened a new avenue to defeat cancer by exploiting selective toxicity against multidrug-resistant (MDR) cancer. In the present study, a clinically used synthetic steroid hormone, danazol, was investigated for its CS properties and cytotoxic mechanisms. Compared with natural hormones, danazol possessed a stronger selective cytotoxicity against MDR cancer cells. Danazol induced the arrest of MDR cancer cells at the G2/M phase and caspase-8–related early apoptosis. Furthermore, in MDR cancer cells, danazol reduced STAT3 phosphorylation as well as the expression of STAT3-regulated genes involved in cell survival, such as c-Myc, CDC25, and CDK1. Danazol also upregulated the cell cycle inhibitor p21 in MDR cancer cells. Supporting the experimental results, docking studies have revealed that danazol can likely bind favourably with STAT3. Taken together, our results suggest that danazol exerts a CS efect by inhibiting the STAT3 pathway in MDR cancer cells and thus provides a possible solution for MDR cancers. Although several medical approaches, including immunotherapy (e.g., immune checkpoint inhibitors) and tar- geted therapy (e.g., tyrosine kinase inhibitors), have been added to cancer treatment, cytotoxic chemotherapeutic agents still play an crucial and frst-line role in clinical practice1,2. However, because of multidrug resistance, patients do not enter remission, and tumours relapse and become insensitive to various structurally unrelated agents, leading to subsequent aggressive tumour growth or metastasis1,2. Previous studies have attributed the multidrug resistance phenomenon to several causes, including the overexpression of ATP-binding cassette (ABC) drug efux transporters, genetic alteration during chemotherapy, rescue of the apoptosis signalling pathway, and damage repair mechanisms3,4. Numerous approaches to combat multidrug-resistant (MDR) cancer have emerged in the past 50 years, such as developing new chemical structures that evade the efux of ABC transporters, combining conventional chemo- therapy with ABC transporter inhibitors, and exploiting MDR cancer cells based on distinct genetic properties compared with their chemosensitive counterparts5. Among the worldwide small-molecule drug screening pro- jects, several research groups have reported that, unlike conventional chemotherapeutic agents that exhibit high resistance to MDR cancer cells, some drugs have the potential to target MDR cancer cells with a low response to sensitive cancer cells. Tis phenomenon is called collateral sensitivity (CS) and provides a prospective opportu- nity for combating MDR cancer6,7. 1Department of Pharmacy, College of Pharmacy, China Medical University, 91 Hsueh-Shih Road, Taichung, 40402, Taiwan, ROC. 2Department of Medicine, College of Medicine, I-Shou University, 8 Yida Road, Kaohsiung, 82445, Taiwan, ROC. 3Department of Obstetrics and Gynecology, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan, ROC. 4Department of Cosmetic Science, Providence University, Taichung, Taiwan, ROC. 5Department of Biomedical Informatics, Asia University, Wufeng, Taichung, 41354, Taiwan, ROC. 6Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, 27599, United States. 7Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, 40447, Taiwan, ROC. 8Department of Pharmacy, China Medical University Hospital, 2 Yude Road, Taichung, 40447, Taiwan, ROC. Ying-Tzu Chang, Yu-Ning Teng and Kun-I Lin contributed equally. Correspondence and requests for materials should be addressed to C.-C.H. (email: [email protected]) SCIENTIFIC REPORTS | (2019) 9:11628 | https://doi.org/10.1038/s41598-019-48169-2 1 www.nature.com/scientificreports/ www.nature.com/scientificreports Figure 1. Structure of danazol. CS efects on cancer cell lines have been demonstrated for a wide range of drugs, including the L-type calcium channel antagonist verapamil8, favonoid desmosdumotin B9,10, glucose analogue 2-deoxy-D-glucose (2-DG)11, iron chelator Dp44mT12, local anaesthetics and narcotics13,14, as well as some natural steroid hormones15–17. Tis novel MDR cancer-combating strategy has been related to several mechanisms, such as reactive oxygen species (ROS) production, energy utilisation sensitivity, extrusion of endogenous substrates required for cell survival, and membrane perturbation. However, results from some studies have been controversial6. In addition, the signal transducer and activator of transcription 3 (STAT3) signalling pathway has been associated with chemotherapeu- tic resistance in several cancers18. Silencing STAT3 may resensitise resistant cancer cells to paclitaxel, doxorubicin, and cisplatin19. More studies are warranted to elucidate the underlying mechanisms for the possible involvement of STAT3 in the CS efect. Among the compounds that exhibited the CS efect, natural steroid hormones are the most promising candi- dates. Under physiological concentrations, progesterone and deoxycorticosterone demonstrated a considerable CS efect on MDR cancer cell lines20. Danazol (Fig. 1) is derived from testosterone and has been prescribed primarily for the treatment of endometriosis since 1971. In light of its diverse biological efects, danazol is also prescribed for ‘of-label’ use in a wide range of disorders21,22. Several studies have reported the cytotoxic efects of danazol alone and in combination with chemotherapeutic agents on leukaemia and breast cancer cells23,24. However, the CS efect of danazol has not been systemically evaluated. Terefore, our study was aimed at charac- terising the possible CS efect of danazol against MDR cancer cells and further elucidating the underlying mech- anisms of CS to identify potential novel targets for future drug design. Results Danazol exhibited CS effect on several MDR cancer cell lines. Three paired parental (HeLaS3, HepG2, and NCI-H460) and MDR (KB/VIN, HepG2/VIN, and NCI-H460/MX20) cancer cell lines were used in SRB assay to screen both traditional chemotherapeutic agents and steroid hormones. From the results, MDR cancer cell lines exhibited strong resistance to chemotherapeutic agents: KB/VIN and HepG2/VIN were 3557.64- and 138.23-fold resistant toward paclitaxel and NCI-H460/MX20 was 51.32- and 39.72- fold resistant toward mitoxantrone and etoposide, respectively (Table 1). Both natural and synthetic hormones were tested in our primary screening for their CS efects on KB/VIN. Te results in Table 2 indicated that the synthetic steroid hormone danazol exhibited the most potent cytotoxicity (0.73 μM) against KB/VIN among the screened compounds (selectivity index (SI) was 33.48). Some natural ster- oid hormones also showed diferent degrees of cytotoxic selectivity toward KB/VIN, while aldosterone and estriol exhibited no diference toward parental and resistant cell lines. Notably, the order of the SI of pregnenolone, progesterone, deoxycorticosterone, and corticosterone corresponded generally to the order of drug metabolism. Te selectivity gradually increased when pregnenolone was metabolized to corticosterone (SI 2.68, 5.21, 8.99 and 7.81). Danazol, the most potent CS compound, was further investigated for selectivity toward other MDR cancer cell lines. It also exhibited strong and moderate selectivity toward HepG2/VIN (SI 211.83) and NCI-H460/MX20 (SI 4.45), demonstrating CS efects across multiple kinds of MDR cancer cell lines (Table 1). The CS efect of danazol was not related to the efux function of P-glycoprotein. Te CS mech- anism is ofen linked to the drug efux pump P-glycoprotein (P-gp), which is responsible for one mechanism leading to the MDR cancer phenotype. Terefore, the relationship between the CS efect of danazol and the expression and function of P-gp was investigated. Danazol was co-administered with a P-gp substrate or inhibitor to evaluate whether the P-gp efux function infuenced the compound’s CS efect. Te cytotoxic IC50 of danazol was not signifcantly altered afer co-treatment with the P-gp substrate vincristine or the P-gp inhibitors verapa- mil and cyclosporin A. Te IC50 values for danazol only, danazol with 100 nM vincristine, danazol with 10 μM verapamil, and danazol with 1 μM cyclosporin A in KB/VIN cells were 0.73 ± 0.04, 0.66 ± 0.02, 0.46 ± 0.11, and 0.49 ± 0.13 μM, respectively. Furthermore, the IC50 values of danazol in the human P-gp stable expression cell SCIENTIFIC REPORTS | (2019) 9:11628 | https://doi.org/10.1038/s41598-019-48169-2 2 www.nature.com/scientificreports/ www.nature.com/scientificreports IC 50 Resistant Selectivity Compound HeLaS3 KB/VIN Fold (RF)a Index (SI)b Danazol (μM) 24.44 ± 1.87 0.73 ± 0.04 33.48 Doxorubicin (nM) 503.74 ± 63.65 12156.70 ± 1.00 24.13 Paclitaxel (nM) 0.78 ± 0.02 2774.96 ± 71.56 3557.64 HepG2 HepG2/VIN Danazol (μM) 25.42 ± 3.48 0.12 ± 0.01 211.83 Paclitaxel (nM) 14.27 ± 2.46 1972.55 ± 23.50 138.23 Vincristine (nM) 75.68 ± 4.87 2457.60 ± 113.96 32.47 NCI-H460 NCI-H460/MX20 Danazol (μM) 79.55 ± 5.05 17.89 ± 0.80 4.45 Doxorubicin (nM) 80.59 ± 2.46 1944.14 ± 41.93 24.12 Etoposide (nM) 666.32 ± 16.90 26464.05 ± 3692 39.72 Mitoxantrone (nM) 81.22 ± 3.81 4168.22 ± 165.84 51.32 Topotecan (nM) 55.33 ± 3.18 1437.22 ± 152.95 25.98 Table 1. Selectivity Index of Danazol on several multidrug-resistant cancer cell lines. aTe resistant fold was calculated by dividing the individual IC50 of MDR cell line (KB/VIN, HepG2/VIN, or NCI-H460/MX20) by b the IC50 of parental cell line (HeLaS3, HepG2, or NCI-H460). Te selectivity index was calculated by dividing the individual IC50 of parental cell line (HeLaS3, HepG2, or NCI-H460) by the IC50 of MDR cell line (KB/VIN, HepG2/VIN, or NCI-H460/MX20).
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