In recent years, there has been an increase in both the incidence and mortality of breast cancer. Globally, breast cancer is ranked as the main root of cancer-related death in women. Multidrug resistance (MDR) is identified as a primary cause of treatment failure in anticancer chemotherapy. This makes multidrug resistance an interesting therapeutic target in breast cancer. Therefore, elucidation of the molecular mechanisms involved in chemoresistance is essential. Phosphodiesterase 5 (PDE5) cross-talks with nitric oxide/cyclic guanosine monophosphate (NO/cGMP), Wnt/β-catenin, and PI3K/Akt signaling pathways to upregulate the expression of ABC transporters and increase cGMP efflux. This enhances multidrug resistance and impacts cellular processes such as proliferation, apoptosis, and angiogenesis. Thus, further research on the identification of possible factors in the reversal of MDR in breast cancer is necessary. Sildenafil is a selective phosphodiesterase type 5 inhibitor that is commonly utilized as first-line therapy in treating erectile dysfunction. Its safety profile and tolerability have encouraged researchers to develop an interest in further investigations into its beneficial uses, especially its chemo-preventive activity in managing breast cancer. In this review, we critically examined the central role played by PDE5 in activating several pathways involved in MDR in breast cancer. Given that sildenafil is a selective PDE5 inhibitor, we provide insight into its modulatory effects and interactions with signaling pathways targeted by PDE5 to overcome MDR in breast cancer.
Citation: Anne A. Adeyanju, Wonderful B. Adebagbo, Olorunfemi R. Molehin, Omolola R. Oyenihi. Exploring the multi-drug resistance (MDR) inhibition property of Sildenafil: phosphodiesterase 5 as a therapeutic target and a potential player in reversing MDR for a successful breast cancer treatment[J]. AIMS Medical Science, 2025, 12(2): 145-170. doi: 10.3934/medsci.2025010
In recent years, there has been an increase in both the incidence and mortality of breast cancer. Globally, breast cancer is ranked as the main root of cancer-related death in women. Multidrug resistance (MDR) is identified as a primary cause of treatment failure in anticancer chemotherapy. This makes multidrug resistance an interesting therapeutic target in breast cancer. Therefore, elucidation of the molecular mechanisms involved in chemoresistance is essential. Phosphodiesterase 5 (PDE5) cross-talks with nitric oxide/cyclic guanosine monophosphate (NO/cGMP), Wnt/β-catenin, and PI3K/Akt signaling pathways to upregulate the expression of ABC transporters and increase cGMP efflux. This enhances multidrug resistance and impacts cellular processes such as proliferation, apoptosis, and angiogenesis. Thus, further research on the identification of possible factors in the reversal of MDR in breast cancer is necessary. Sildenafil is a selective phosphodiesterase type 5 inhibitor that is commonly utilized as first-line therapy in treating erectile dysfunction. Its safety profile and tolerability have encouraged researchers to develop an interest in further investigations into its beneficial uses, especially its chemo-preventive activity in managing breast cancer. In this review, we critically examined the central role played by PDE5 in activating several pathways involved in MDR in breast cancer. Given that sildenafil is a selective PDE5 inhibitor, we provide insight into its modulatory effects and interactions with signaling pathways targeted by PDE5 to overcome MDR in breast cancer.
| [1] |
Barrios CH (2022) Global challenges in breast cancer detection and treatment. Breast 62: S3-S6. https://doi.org/10.1016/j.breast.2022.02.003 
|
| [2] |
Wilkinson L, Gathani T (2022) Understanding breast cancer as a global health concern. Br J Radiol 95: 20211033. https://doi.org/10.1259/bjr.20211033
|
| [3] |
Konieczna J, Chaplin A, Paz-Graniel I, et al. (2025) Adulthood dietary and lifestyle patterns and risk of breast cancer: Global Cancer Update Programme (CUP Global) systematic literature review. Am J Clin Nutr 121: 14-31. https://doi.org/10.1016/j.ajcnut.2024.10.003
|
| [4] |
Bray F, McCarron P, Parkin DM (2004) The changing global patterns of female breast cancer incidence and mortality. Breast Cancer Res 6: 229-239. https://doi.org/10.1186/bcr932
|
| [5] |
Van Harten WH, Wind A, De Paoli P, et al. (2016) Actual costs of cancer drugs in 15 European countries. Lancet Oncol 17: 18-20. https://doi.org/10.1016/S1470-2045(15)00486-6
|
| [6] | Malik JA, Jan R, Ahmed S, et al. (2022) Breast cancer drug repurposing a tool for a challenging disease, In: Saxena, S.K. Editor. Drug Repurposing—Molecular Aspects and Therapeutic Applications . https://doi.org/10.5772/intechopen.101378 |
| [7] |
Jourdan JP, Bureau R, Rochais C, et al. (2020) Drug repositioning: a brief overview. J Pharm Pharmacol 72: 1145-1151. https://doi.org/10.1111/jphp.13273
|
| [8] |
Preston IR, Klinger JR, Houtches J, et al. (2005) Acute and chronic effects of sildenafil in patients with pulmonary arterial hypertension. Respir Med 99: 1501-1510. https://doi.org/10.1016/j.rmed.2005.03.026
|
| [9] |
Stratton MR, Campbell PJ, Futreal PA (2009) The cancer genome. Nature 458: 719-724. https://doi.org/10.1038/nature07943
|
| [10] | Ataollahi MR, Sharifi J, Paknahad MR, et al. (2015) Breast cancer and associated factors: a review. J Med Life 8: 6-11. |
| [11] | Akbar M, Akbar K, Naveed D (2014) Frequency and correlation of molecular subtypes of breast cancer with clinicopathological features. J Ayub Med Coll Abbottabad 26: 290-293. |
| [12] |
Amjad A, Khan IK, Kausar Z, et al. (2018) Risk factors in breast cancer progression and current advances in therapeutic approaches to knockdown breast cancer. Clin Med Biochem 4. https://doi.org/10.4172/2471-2663.1000137
|
| [13] |
Zengel B, Yararbas U, Duran A, et al. (2015) Comparison of the clinicopathological features of invasive ductal, invasive lobular, and mixed (invasive ductal + invasive lobular) carcinoma of the breast. Breast Cancer 22: 374-381. https://doi.org/10.1007/s12282-013-0489-8
|
| [14] |
Ward EM, DeSantis CE, Lin CC, et al. (2015) Cancer statistics: breast cancer in situ. CA Cancer J Clin 65: 481-495. https://doi.org/10.3322/caac.21321
|
| [15] |
Miklikova S, Trnkova L, Plava J, et al. (2021) The role of BRCA1/2-mutated tumor microenvironment in breast cancer. Cancers 13: 575. https://doi.org/10.3390/cancers13030575
|
| [16] |
Couto E, Hemminki K (2007) Estimates of heritable and environmental components of familial breast cancer using family history information. Br J Cancer 96: 1740-1742. https://doi.org/10.1038/sj.bjc.6603753
|
| [17] |
Pervaiz R (2017) Genetic mutations associated with breast cancer in Pakistan. Malays J Med Biol Res 4: 153-158. https://doi.org/10.18034/mjmbr.v4i2.439
|
| [18] | Menhas R, Umer S (2015) Breast cancer among Pakistani women. Iran J Public Health 44: 586-587. |
| [19] |
Zheng G, Yu H, Hemminki A, et al. (2017) Familial associations of female breast cancer with other cancers. Int J Cancer 141: 2253-2259. https://doi.org/10.1002/ijc.30927
|
| [20] |
Tinsley HN, Gary BD, Keeton AB, et al. (2011) Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/β-catenin-mediated transcription in human breast tumor cells. Cancer Prev Res 4: 1275-1284. https://doi.org/10.1158/1940-6207.CAPR-11-0095
|
| [21] |
Bae SY, Kim S, Lee JH, et al. (2015) Poor prognosis of single hormone receptor- positive breast cancer: similar outcome as triple-negative breast cancer. BMC Cancer 15: 138. https://doi.org/10.1186/s12885-015-1121-4
|
| [22] | Ayoub NM, Al-Shami KM, Yaghan RJ (2019) Immunotherapy for HER2-positive breast cancer: recent advances and combination therapeutic approaches. Breast Cancer 11: 53-69. https://doi.org/10.2147/BCTT.S175360 |
| [23] |
Fabbro M, Savage K, Hobson K, et al. (2004) BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage. J Biol Chem 279: 31251-31258. https://doi.org/10.1074/jbc.M405372200
|
| [24] |
Kast K, Rhiem K, Wappenschmidt B, et al. (2016) Prevalence of BRCA1/2 germline mutations in 21401 families with breast and ovarian cancer. J Med Genet 53: 465-471. https://doi.org/10.1136/jmedgenet-2015-103672
|
| [25] |
Kuchenbaecker KB, Hopper JL, Barnes DR, et al. (2017) Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317: 2402-2416. https://doi.org/10.1001/jama.2017.7112
|
| [26] |
Mavaddat N, Barrowdale D, Andrulis IL, et al. (2012) Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 21: 134-147. https://doi.org/10.1158/1055-9965.EPI-11-0775
|
| [27] |
Shiovitz S, Korde LA (2015) Genetics of breast cancer: a topic in evolution. Ann Oncol 26: 1291-1299. https://doi.org/10.1093/annonc/mdv022
|
| [28] |
Tan MH, Mester JL, Ngeow J, et al. (2012) Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res 18: 400-407. https://doi.org/10.1158/1078-0432.CCR-11-2283
|
| [29] |
Lim W, Olschwang S, Keller JJ, et al. (2004) Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology 126: 1788-1794. https://doi.org/10.1053/j.gastro.2004.03.014
|
| [30] |
Sharma S, Sambyal V, Guleria K, et al. (2014) Tp53 polymorphisms in sporadic north Indian breast cancer patients. Asian Pac J Cancer Prev 15: 6871-6879. https://doi.org/10.7314/apjcp.2014.15.16.6871
|
| [31] |
Gasco M, Shami S, Crook T (2002) The p53 pathway in breast cancer. Breast Cancer Res 4. https://doi.org/10.1186/bcr426
|
| [32] | Al-Joudi FS, Iskandar ZA, Rusli J (2008) The expression of p53 in invasive ductal carcinoma of the breast: a study in the north-east states of Malaysia. Med J Malaysia 63: 96-99. |
| [33] |
Koo MM, von Wagner C, Abel GA, et al. (2017) Typical and atypical presenting symptoms of breast cancer and their associations with diagnostic intervals: evidence from a national audit of cancer diagnosis. Cancer Epidemiol 48: 140-146. https://doi.org/10.1016/j.canep.2017.04.010
|
| [34] |
Gentile F, Elmenoufy AH, Ciniero G, et al. (2019) Computer-aided drug design of small molecule inhibitors of the ERCC1-XPF protein-protein interaction. Chem Biol Drug Des 95: 460-471. https://doi.org/10.1111/cbdd.13660
|
| [35] |
Rosell R, Taron M, Ariza A, et al. (2004) Molecular predictors of response to chemotherapy in lung cancer. Semin Oncol 31: 20-27. https://doi.org/10.1053/j.seminoncol.2003.12.011
|
| [36] |
Mantovani F, Collavin L, Del Sal G (2019) Mutant p53 as a guardian of the cancer cell. Cell Death Differ 26: 199-212. https://doi.org/10.1038/s41418-018-0246-9
|
| [37] |
Hientz K, Mohr A, Bhakta-Guha D, et al. (2017) The role of p53 in cancer drug resistance and targeted chemotherapy. Oncotarget 8: 8921-8946. https://doi.org/10.18632/oncotarget.13475
|
| [38] |
Katzenellenbogen JA, Mayne CG, Katzenellenbogen BS, et al. (2018) Structural underpinnings of estrogen receptor mutations in endocrine therapy resistance. Nat Rev Cancer 18: 377-388. https://doi.org/10.1038/s41568-018-0001-z
|
| [39] |
Ham IH, Oh HJ, Jin H, et al. (2019) Targeting interleukin-6 as a strategy to overcome stroma-induced resistance to chemotherapy in gastric cancer. Mol Cancer 18: 68. https://doi.org/10.1186/s12943-019-0972-8
|
| [40] |
Wang Y, Qu Y, Niu XL, et al. (2011) Autocrine production of interleukin-8 confers cisplatin and paclitaxel resistance in ovarian cancer cells. Cytokine 56: 365-375. https://doi.org/10.1016/j.cyto.2011.06.005
|
| [41] |
Song S, Wientjes MG, Gan Y, et al. (2000) Fibro-blast growth factors: an epigenetic mechanism of broad-spectrum resistance to anticancer drugs. Proc Natl Acad Sci U S A 97: 8658-8663. https://doi.org/10.1073/pnas.140210697
|
| [42] |
Singh S (2015) Cytoprotective and regulatory functions of glutathione-S-transferases in cancer cell proliferation and cell death. Cancer Chemother Pharmacol 75: 1-15. https://doi.org/10.1007/s00280-014-2566-x
|
| [43] |
Jena MK, Janjanam J (2018) Role of extracellular matrix in breast cancer development: a brief update. F1000Res 7: 274. https://doi.org/10.12688/f1000research.14133.2
|
| [44] |
Bukowski K, Kciuk M, Kontek R (2020) Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci 21: 3233. https://doi.org/10.3390/ijms21093233
|
| [45] | Wang X, Zhang H, Chen X (2019) Drug resistance and combating drug resistance in cancer. Cancer Drug Resist 2: 141-160. https://doi.org/10.20517/cdr.2019.10 |
| [46] |
Mesci S, Marakli S, Yazgan B, et al. (2019) The effect of ATP-binding cassette (ABC) transporters in human cancers. Int J Sci Lett 1: 14-19. https://doi.org/10.38058/IJSL.594000
|
| [47] |
Wu CP, Hsiao SH, Huang YH, et al. (2020) Sitravatinib sensitizes ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs. Cancers 12: 195. https://doi.org/10.3390/cancers12010195
|
| [48] |
Souza PS, Madigan JP, Gillet JP, et al. (2015) Expression of the multidrug transporter P-glycoprotein is inversely related to that of apoptosis-associated endogenous TRAIL. Exp Cell Res 336: 318-328. https://doi.org/10.1016/j.yexcr.2015.06.005
|
| [49] |
Gorrini I, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12: 931-947. https://doi.org/10.1038/nrd4002
|
| [50] |
Zhang J, Wang X, Vikash V, et al. (2016) ROS and ROS-mediated cellular signaling. Oxid Med Cell Longev 2016: 4350965. https://doi.org/10.1155/2016/4350965
|
| [51] |
Villeneuve N, Lau A, Zhang DD (2010) Regulation of the Nrf2-Keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin-ring ubiquitin ligases. Antioxid Redox Signal 13: 1699-1712. https://doi.org/10.1089/ars.2010.3211
|
| [52] |
Rushmore TH, Pickett CB (1990) Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. J Biol Chem 265: 14648-14653.
|
| [53] |
Otsuki A, Yamamoto M (2020) Cis-element architecture of Nrf2-sMaf heterodimer binding sites and its relation to diseases. Arch Pharm Res 43: 275-285. https://doi.org/10.1007/s12272-019-01193-2
|
| [54] |
Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45: 51-88. https://doi.org/10.1146/annurev.pharmtox.45.120403.095857
|
| [55] |
Sau A, Pellizzari Tregno F, Valentino F, et al. (2010) Glutathione transferases and development of new principles to overcome drug resistance. Arch Biochem Biophys 500: 116-122. https://doi.org/10.1016/j.abb.2010.05.012
|
| [56] |
Meijerman I, Beijnen JH, Schellens JH (2008) Combined action and regulation of phase II enzymes and multidrug resistance proteins in multidrug resistance in cancer. Cancer Treat Rev 34: 505-520. https://doi.org/10.1016/j.ctrv.2008.03.002
|
| [57] |
Laborde E (2010) Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death. Cell Death Differ 17: 1373-1380. https://doi.org/10.1038/cdd.2010.80
|
| [58] |
Karin M, Gallagher E (2005) From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance. IUBMB Life 57: 283-295. https://doi.org/10.1080/15216540500097111
|
| [59] |
Wu Y, Fan Y, Xue B, et al. (2006) Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals. Oncogene 25: 5787-5800. https://doi.org/10.1038/sj.onc.1209576
|
| [60] |
Ho GY, Woodward N, Coward JI (2016) Cisplatin versus carboplatin: comparative review of therapeutic management in solid malignancies. Crit Rev Oncol Hematol 102: 37-46. https://doi.org/10.1016/j.critrevonc.2016.03.014
|
| [61] |
Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22: 7265-7279. https://doi.org/10.1038/sj.onc.1206933
|
| [62] |
Pasello M, Michelacci F, Scionti I, et al. (2008) Overcoming glutathione S-transferase P1-related cisplatin resistance in osteosarcoma. Cancer Res 68: 6661-6668. https://doi.org/10.1158/0008-5472.can-07-5840
|
| [63] | Kankotia S, Stacpoole PW (2014) Dichloroacetate and cancer: new home for an orphan drug?. Biochim Biophys Acta 1846: 617-629. https://doi.org/10.1016/j.bbcan.2014.08.005 |
| [64] |
Jahn SC, Solayman MH, Lorenzo RJ, et al. (2016) GSTZ1 expression and chloride concentrations modulate sensitivity of cancer cells to dichloroacetate. Biochim Biophys Acta 1860: 1202-1210. https://doi.org/10.1016/j.bbagen.2016.01.024
|
| [65] |
Chen Y, Li Y, Huang L, et al. (2021) Antioxidative stress: inhibiting reactive oxygen species production as a cause of radioresistance and chemoresistance. Oxid Med Cell Longev 2021: 6620306. https://doi.org/10.1155/2021/6620306
|
| [66] |
Pirpour Tazehkand A, Salehi R, Velaei K, et al. (2020) The potential impact of trigonelline loaded micelles on Nrf2 suppression to overcome oxaliplatin resistance in colon cancer cells. Mol Biol Rep 47: 5817-5829. https://doi.org/10.1007/s11033-020-05650-w
|
| [67] |
Perez EA (2009) Impact, mechanisms, and novel chemotherapy strategies for overcoming resistance to anthracyclines and taxanes in metastatic breast cancer. Breast Cancer Res Treat 114: 195-201. https://doi.org/10.1007/s10549-008-0005-6
|
| [68] |
Szakacs G, Paterson JK, Ludwig JA, et al. (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5: 219-234. https://doi.org/10.1038/nrd1984
|
| [69] |
Liang XJ, Chen C, Zhao Y, et al. (2010) Circumventing tumor resistance to chemotherapy by nanotechnology. Methods Mol Biol 596: 467-488. https://doi.org/10.1007/978-1-60761-416-6_21
|
| [70] |
Saxena M, Stephens MA, Pathak H, et al. (2011) Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death Dis 2: e179. https://doi.org/10.1038/cddis.2011.61
|
| [71] |
Ambudkar SV, Dey S, Hrycyna CA, et al. (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 39: 361-398. https://doi.org/10.1146/annurev.pharmtox.39.1.361
|
| [72] |
Shen DW, Goldenberg S, Pastan I, et al. (2000) Decreased accumulation of [14C] carboplatin in human cisplatin-resistant cells results from reduced energy-dependent uptake. J Cell Physiol 183: 108-116. https://doi.org/10.1002/(SICI)1097-4652(200004)183:1<108::AID-JCP13>3.0.CO;2-4
|
| [73] |
Lowe SW, Ruley HE, Jacks T, et al. (1993) p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74: 957-967. https://doi.org/10.1016/0092-8674(93)90719-7
|
| [74] |
Liu Y, Han TY, Giuliano AE, et al. (2001) Ceramide glycosylation potentiates cellular multidrug resistance. FASEB J 15: 719-730. https://doi.org/10.1096/fj.00-0223com
|
| [75] |
Di X, Gennings C, Bear HD, et al. (2010) Influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to chemotherapy in breast tumor cells. Breast Cancer Res Treat 124: 349-360. https://doi.org/10.1007/s10549-010-0765-7
|
| [76] |
Ahmed WS, Geethakumari AM, Biswas KH (2021) Phosphodiesterase 5 (PDE5): structure-function regulation and therapeutic applications of inhibitors. Biomed Pharmacother 134: 111128. https://doi.org/10.1016/j.biopha.2020.111128
|
| [77] |
Al-Shboul O, Mahavadi S, Sriwai W, et al. (2013) Differential expression of multidrug resistance protein 5 and phosphodiesterase 5 and regulation of cGMP levels in phasic and tonic smooth muscle. Am J Physiol Gastrointest Liver Physiol 305: G314-G324. https://doi.org/10.1152/ajpgi.00457.2012
|
| [78] |
Paronetto MP, Crescioli C (2024) Rethinking of phosphodiesterase 5 inhibition: the old, the new and the perspective in human health. Front Endocrinol 15: 1461642. https://doi.org/10.3389/fendo.2024.1461642
|
| [79] |
Peng T, Gong J, Jin Y, et al. (2018) Inhibitors of phosphodiesterase as cancer therapeutics. Eur J Med Chem 150: 742-756. https://doi.org/10.1016/j.ejmech.2018.03.046
|
| [80] |
Catalano S, Campana A, Giordano C, et al. (2016) Expression and function of phosphodiesterase type 5 in human breast cancer cell lines and tissues: implications for targeted therapy. Clin Cancer Res 22: 2271-2282. https://doi.org/10.1158/1078-0432.ccr-15-1900
|
| [81] |
Gong L, Lei Y, Tan X, et al. (2019) Propranolol selectively inhibits cervical cancer cell growth by suppressing the cGMP/PKG pathway. Biomed Pharmacother 111: 1243-1248. https://doi.org/10.1016/j.biopha.2019.01.027
|
| [82] |
Lee K, Piazza GA (2017) The interaction between the Wnt/β-catenin signaling cascade and PKG activation in cancer. J Biomed Res 31: 189-196. https://doi.org/10.7555/JBR.31.20160133
|
| [83] |
Jedlitschky G, Burchell B, Keppler D (2000) The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. J Biol Chem 275: 30069-30074. https://doi.org/10.1074/jbc.M005463200
|
| [84] |
Zhang Z, Huang W, Huang D, et al. (2025) Repurposing of phosphodiesterase-5 inhibitor sildenafil as a therapeutic agent to prevent gastric cancer growth through suppressing c-MYC stability for IL-6 transcription. Commun Biol 8: 85. https://doi.org/10.1038/s42003-025-07519-9
|
| [85] |
Ribeiro E, Costa B, Vasques-Nóvoa F, et al. (2023) In vitro drug repurposing: focus on vasodilators. Cells 12: 671. https://doi.org/10.3390/cells12040671
|
| [86] |
Jang GB, Kim JY, Cho SD, et al. (2015) Blockade of Wnt/β-catenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype. Sci Rep 5: 12465. https://doi.org/10.1038/srep12465
|
| [87] |
Raut D, Vora A, Bhatt LK (2022) The Wnt/β-catenin pathway in breast cancer therapy: a pre- clinical perspective of its targeting for clinical translation. Expert Rev Anticancer Ther 22: 97-114. https://doi.org/10.1080/14737140.2022.2016398
|
| [88] |
Wang JQ, Wu ZX, Yang Y, et al. (2021) ATP-binding cassette (ABC) transporters in cancer: a review of recent updates. J Evid Based Med 14: 232-256. https://doi.org/10.1111/jebm.12434
|
| [89] |
Duan C, Yu M, Xu J, et al. (2023) Overcoming Cancer Multi-drug Resistance (MDR): Reasons, mechanisms, nanotherapeutic solutions, and challenges. Biomed Pharmacother 162: 114643. https://doi.org/10.1016/j.biopha.2023.114643
|
| [90] | Koehn LM (2022) ABC transporters: an overview. https://doi.org/10.1007/978-3-030-51519-5_76-1 |
| [91] |
Engle K, Kumar G (2022) Cancer multidrug-resistance reversal by ABCB1 inhibition: a recent update. Eur J Med Chem 239: 114542. https://doi.org/10.1016/j.ejmech.2022.114542
|
| [92] |
Sajid A, Rahman H, Ambudkar SV (2023) Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters. Nat Rev Cancer 23: 762-779. https://doi.org/10.1038/s41568-023-00612-3
|
| [93] |
Skinner KT, Palkar AM, Hong AL (2023) Genetics of ABCB1 in cancer. Cancers 15: 4236. https://doi.org/10.3390/cancers15174236
|
| [94] |
Zhou HM, Zhang JG, Zhang X, et al. (2021) Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents. Signal Transduct Target Ther 6: 62. https://doi.org/10.1038/s41392-020-00430-1
|
| [95] |
Ni Y, Zhou X, Yang J, et al. (2021) The role of tumor-stroma interactions in drug resistance within tumor microenvironment. Front Cell Dev Biol 9: 637675. https://doi.org/10.3389/fcell.2021.637675
|
| [96] | Karunarathna I, De Alvis K, Gunasena P, et al. (2024) The impact of sildenafil on quality of life: evidence from clinical studies. In: Comprehensive Insights on Intensive Care, Anaesthesia, and Pain Management: An Article Compilation. Charlottesville: UVA-Clinical Pharmacology, 179-182. |
| [97] |
Chhonker SK, Rawat D, Koiri RK (2022) Repurposing PDE5 inhibitor tadalafil and sildenafil as anticancer agent against hepatocellular carcinoma via targeting key events of glucose metabolism and multidrug resistance. J Biochem Mol Toxicol 36: e23100. https://doi.org/10.1002/jbt.23100
|
| [98] |
Bhattacharjya D, Sivalingam N (2024) Mechanism of 5-fluorouracil induced resistance and role of piperine and curcumin as chemo-sensitizers in colon cancer. Naunyn Schmiedebergs Arch Pharmacol 397: 8445-8475. https://doi.org/10.1007/s00210-024-03189-2
|
| [99] |
Gu Y, Yang R, Zhang Y, et al. (2025) Molecular mechanisms and therapeutic strategies in overcoming chemotherapy resistance in cancer. Mol Biomed 6: 2. https://doi.org/10.1186/s43556-024-00239-2
|
| [100] |
Ebrahimnezhad M, Asl SH, Rezaie M, et al. (2024) lncRNAs: new players of cancer drug resistance via targeting ABC transporters. IUBMB Life 76: 883-921. https://doi.org/10.1002/iub.2888
|
| [101] | Goebel J, Chmielewski J, Hrycyna CA (2021) The roles of the human ATP-binding cassette transporters P-glycoprotein and ABCG2 in multidrug resistance in cancer and at endogenous sites: future opportunities for structure-based drug design of inhibitors. Cancer Drug Resist 4: 784-804. https://doi.org/10.20517/cdr.2021.19 |
| [102] |
Angelis I, Moussis V, Tsoukatos DC, et al. (2021) Multidrug resistance protein 4 (MRP4/ABCC4): a suspected efflux transporter for human's platelet activation. Protein Pept Lett 28: 983-995. https://doi.org/10.2174/0929866528666210505120659
|
| [103] |
Yin Q, Zheng X, Song Y, et al. (2023) Decoding signaling mechanisms: unraveling the targets of guanylate cyclase agonists in cardiovascular and digestive diseases. Front Pharmacol 14: 1272073. https://doi.org/10.3389/fphar.2023.1272073
|
| [104] | Kuzmiszyn AK (2023) Temperature-dependent effects of phosphodiesterase inhibitors for cardiovascular support in hypothermic patients-Effects on cellular elimination of cAMP and cGMP. Available from: https://hdl.handle.net/10037/31584 |
| [105] |
Liu R, Chen Y, Liu G, et al. (2020) PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis 11: 797. https://doi.org/10.1038/s41419-020-02998-6
|
| [106] |
He Y, Sun MM, Zhang GG, et al. (2021) Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther 6: 425. https://doi.org/10.1038/s41392-021-00828-5
|
| [107] |
Dong C, Wu J, Chen Y (2021) Activation of PI3K/AKT/mTOR pathway causes drug resistance in breast cancer. Front Pharmacol 12: 628690. https://doi.org/10.3389/FPHAR.2021.628690
|
| [108] |
Booth L, Albers T, Roberts JL, et al. (2016) Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo. Oncotarget 7: 40398-40417. https://doi.org/10.18632/oncotarget.9752
|
| [109] |
Greish K, Sawa T, Fang J, et al. (2004) SMA-doxorubicin, a new polymeric micellar drug for effective targeting to solid tumours. J Control Release 97: 219-230. https://doi.org/10.1016/j.jconrel.2004.03.027
|
| [110] |
Black KL, Yin D, Ong JM, et al. (2008) PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model. Brain Res 1230: 290-302. https://doi.org/10.1016/j.brainres.2008.06.122
|
| [111] |
Mehrotra N, Gupta M, Kovar A, et al. (2007) The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy. Int J Impot Res 19: 253-264. https://doi.org/10.1038/sj.ijir.3901522
|
| [112] |
Zhang P, Zhang Y, Ding X, et al. (2020) Enhanced nanoparticle accumulation by tumor-acidity-activatable release of sildenafil to induce vasodilation. Biomater Sci 8: 3052-3062. https://doi.org/10.1039/D0BM00466A
|
| [113] |
Abd El-Aziz YS, Spillane AJ, Jansson PJ, et al. (2021) Role of ABCB1 in mediating chemoresistance of triple-negative breast cancers. Biosci Rep 41: BSR20204092. https://doi.org/10.1042/BSR20204092
|
| [114] |
Rad SK, Yeo KKL, Li R, et al. (2025) Enhancement of doxorubicin efficacy by Bacopaside II in triple-negative breast cancer cells. Biomolecules 15: 55. https://doi.org/10.3390/biom15010055
|
| [115] |
Chen JJ, Sun YL, Tiwari AK, et al. (2012) PDE5 inhibitors, sildenafil and vardenafil, reverse multidrug resistance by inhibiting the efflux function of multidrug resistance protein 7 (ATP-binding Cassette C10) transporter. Cancer Sci 103: 1531-1537. https://doi.org/10.1111/j.1349-7006.2012.02328.x
|
| [116] |
El-Naa MM, Othman M, Younes S (2016) Sildenafil potentiates the antitumor activity of cisplatin by induction of apoptosis and inhibition of proliferation and angiogenesis. Drug Des Dev Ther 10: 3661-3672. https://doi.org/10.2147/DDDT.S107490
|
| [117] |
Booth L, Roberts JL, Cruickshanks N, et al. (2015) PDE5 inhibitors enhance celecoxib killing in multiple tumor types. J Cell Physiol 230: 1115-1127. https://doi.org/10.1002/jcp.24843
|
| [118] |
Hassanvand F, Mohammadi T, Ayoubzadeh N, et al. (2020) Sildenafil enhances cisplatin-induced apoptosis in human breast adenocarcinoma cells. J Cancer Res Ther 16: 1412-1418. https://doi.org/10.4103/jcrt.JCRT_675_19
|
| [119] |
Greish K, Fateel M, Abdelghany S, et al. (2018) Sildenafil citrate improves the delivery and anticancer activity of doxorubicin formulations in a mouse model of breast cancer. J Drug Target 26: 610-615. https://doi.org/10.1080/1061186X.2017.1405427
|
| [120] |
Webb T, Carter J, Roberts JL, et al. (2015) Celecoxib enhances [sorafenib + sildenafil] lethality in cancer cells and reverts platinum chemotherapy resistance. Cancer Biol Ther 16: 1660-1670. https://doi.org/10.1080/15384047.2015.1099769
|
| [121] |
Chen L, Liu Y, Becher A, et al. (2020) Sildenafil triggers tumor lethality through altered expression of HSP90 and degradation of PKD2. Carcinogenesis 41: 1421-1431. https://doi.org/10.1093/carcin/bgaa001
|
Figures(4) / Tables(1)
Anne A. Adeyanju, Wonderful B. Adebagbo, Olorunfemi R. Molehin, Omolola R. Oyenihi. Exploring the multi-drug resistance (MDR) inhibition property of Sildenafil: phosphodiesterase 5 as a therapeutic target and a potential player in reversing MDR for a successful breast cancer treatment[J]. AIMS Medical Science, 2025, 12(2): 145-170. doi: 10.3934/medsci.2025010
DownLoad: