Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 1614 2024-02-27 14:14:02 |
2 references update and layout -1 word(s) 1613 2024-03-05 09:18:49 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Merjaneh, N.; Hajjar, M.; Lan, Y.; Kalinichenko, V.V.; Kalin, T.V. FOXM1 Inhibitors in Combination with Cytotoxic Chemotherapy. Encyclopedia. Available online: https://encyclopedia.pub/entry/55548 (accessed on 17 April 2024).
Merjaneh N, Hajjar M, Lan Y, Kalinichenko VV, Kalin TV. FOXM1 Inhibitors in Combination with Cytotoxic Chemotherapy. Encyclopedia. Available at: https://encyclopedia.pub/entry/55548. Accessed April 17, 2024.
Merjaneh, Nawal, Mona Hajjar, Ying-Wei Lan, Vladimir V. Kalinichenko, Tanya V. Kalin. "FOXM1 Inhibitors in Combination with Cytotoxic Chemotherapy" Encyclopedia, https://encyclopedia.pub/entry/55548 (accessed April 17, 2024).
Merjaneh, N., Hajjar, M., Lan, Y., Kalinichenko, V.V., & Kalin, T.V. (2024, February 27). FOXM1 Inhibitors in Combination with Cytotoxic Chemotherapy. In Encyclopedia. https://encyclopedia.pub/entry/55548
Merjaneh, Nawal, et al. "FOXM1 Inhibitors in Combination with Cytotoxic Chemotherapy." Encyclopedia. Web. 27 February, 2024.
FOXM1 Inhibitors in Combination with Cytotoxic Chemotherapy
Edit

Forkhead box M1 (FOXM1) is a transcription factor in the forkhead (FOX) family, which is required for cellular proliferation in normal and neoplastic cells. FOXM1 is highly expressed in many different cancers, and its expression is associated with a higher tumor stage and worse patient-related outcomes. Abnormally high expression of FOXM1 in cancers compared to normal tissue makes FOXM1 an attractive target for pharmacological inhibition. FOXM1-inhibiting agents and specific FOXM1-targeted small-molecule inhibitors have been developed in the lab and some of them have shown promising efficacy and safety profiles in mouse models. While the future goal is to translate FOXM1 inhibitors to clinical trials, potential synergistic drug combinations can maximize anti-tumor efficacy while minimizing off-target side effects.

combination therapies FOXM1 inhibitor cancer

1. Introduction

Forkhead box M1 (FOXM1) protein is a member of the forkhead box (FOX) transcription factor family that shares homology in the Winged Helix/Forkhead DNA-binding domain [1][2][3]. FOXM1 is highly expressed during normal embryogenesis and is extinguished in terminally differentiated cells [4]. Homozygous deletion of Foxm1 in mice is lethal; embryos die in utero between 13.5 and 17.5 days of gestation due to severe proliferation defects in multiple organs, including the heart, liver, and blood vessels [5][6]. Conditional deletion of Foxm1 in various mice cell types inhibits cell proliferation [4][7][8][9][10][11][12][13], whereas the overexpression of Foxm1 accelerates cell proliferation [14][15][16][17] and prevents age-related defects in cell cycle progression [18]. FOXM1 also regulates the inflammatory response and intracellular metabolic processes [19][20][21][22][23][24][25]. Consistent with the important role of FOXM1 in cell cycle progression, FOXM1 expression is increased during carcinogenesis [26]. The human FOXM1 gene is located on the chromosomal band 12p13 [27], which is frequently amplified in different cancers, including prostate cancer [28][29], breast adenocarcinoma [30], head and neck squamous cell carcinoma [31], nasopharyngeal carcinoma [32], and cervical squamous carcinoma [33]. The increased level of FOXM1 in different types of cancer induces cancer progression, invasion, metastasis, and tumor-associated angiogenesis [34][35][36]. The differential expression of FOXM1 in tumors compared to normal tissues makes it an attractive target for pharmacological inhibition [26][37]. Several FOXM1 inhibitors have been evaluated in pre-clinical studies. However, no compound has been advanced to clinical trials. Several natural products like honokiol, curcumin, genistein, solanum incanum extract, and diarylheptanoids were found to decrease the expression of FOXM1 and its target genes [38][39][40][41] or attenuate the FOXM1 gene network [42]. Cellular-based in vitro assays uncovered the FOXM1-inhibitory activities of thiazole antibiotics, including Siomycin A and thiostrepton [43]. It was shown that the anti-FOXM1 activity of these compounds was executed through proteasome inhibition. Furthermore, pharmacological proteasome inhibitors, such as bortezomib and carfilzomib, inhibited FOXM1 activity to the same level [44]. However, these FOXM1 inhibitors are not specific to FOXM1 and may carry severe off-targeted side effects [45]. Therefore, there has been a movement to identify compounds that can specifically bind and inhibit FOXM1. Among them are RCM-1, STL427944, and STL001, representing the small molecules that inhibit FOXM1 nuclear translocation and induce its cytoplasmic degradation [46][47][48][49]. RCM-1 has shown excellent anti-tumor activity against different tumor cell lines and in mouse tumor xenografts without observed toxic side effects [47][50]. One mechanism by which RCM-1 inhibits FOXM1 is the disruption of protein–protein interactions between FOXM1 and β-catenin, a key receptor of the canonical Wnt signaling pathway. The inhibition of FOXM1–β-catenin interactions by RCM-1 results in the degradation of both proteins, leading to a robust anti-tumor effect [47]. Other specific FOXM1 inhibitors, such as FDI-6 and XST-20, bind to the FOXM1 DNA-binding domain, which subsequently prevents FOXM1 interaction with DNA and decreases FOXM1 transcriptional activity without a decrease in protein level [51][52].

2. FOXM1 Inhibitors in Combination with Cytotoxic Chemotherapy

Cytotoxic chemotherapy is still the cornerstone for the management of most pediatric and adult malignancies. They are divided into categories based on their mechanism of action. Multiagent chemotherapy is frequently used to overcome cancer intrinsic resistance (Goldie–Coldman hypothesis). However, refractory and relapsed tumors are often encountered in clinical practice, with very few options left for salvage treatment. While chemotherapy resistance is often multifactorial, FOXM1 overexpression has been repeatedly observed in many resistant solid tumors [53][54]. Because FOXM1 has a critical role in DNA repair after cell exposure to DNA-damaging agents, its expression in resistant cells is a defensive mechanism to escape cell death. FOXM1 regulates the transcription of multiple DNA damage repair (DDR) proteins and enhances DNA single- and double-strand break repair [53]. Furthermore, FOXM1 protein levels correlate with genomic instability and aneuploidy [26][55], and chromosomal instability is frequently linked to chemotherapy resistance and poor patient prognosis [56][57]. Collectively, FOXM1 is an attractive therapeutic target to be considered as an addition to chemotherapy to improve outcomes and prevent chemotherapy-resistant tumors (Figure 1).
Figure 1. FOXM1 Inhibitor-Based Combination Therapies in Upfront Regimens. Created with BioRender.com (accessed on 5 December 2023).

2.1. Combination with Alkylating Agents

a. Platinum analogs: Cisplatin and carboplatin work by forming DNA adducts that disrupt DNA structure, leading to irreparable damage and apoptosis initiation. Cisplatin-resistant ovarian and oral carcinoma cells express a higher level of FOXM1 [58][59]. Not surprisingly, FOXM1 overexpression correlates with the expression of multiple DNA damage response proteins such as BRCA2, XRCC1, and EXO1 [54][60], likely enhancing the efficiency of DNA repair and maintaining cell survival. FOXM1 also induces β-catenin expression, nuclear localization, and activation, promoting the epithelial-to-mesenchymal transition (EMT) and stem cell phenotype in ovarian cancer cells [58]. Concurrent treatment with cisplatin and a FOXM1 inhibitor restores cisplatin’s anti-tumor activity. Combination treatment exhibits an enhanced proapoptotic activity in contrast to a single agent in ovarian cancer and oral squamous cell carcinoma xenografts [58][59].
b. Temozolomide (TMZ) is an alkylator that breaks DNA into double-strand DNA fragments. It is widely used for the treatment of high-grade gliomas. However, resistance to TMZ is usually inescapable and correlates with worse survival outcomes. Multiple studies demonstrated an increased FOXM1 level in TMZ-resistant cells [61][62][63]. FOXM1 expression promotes DNA repair via the upregulation of RFC5 and Rad 51 proteins [62][63]. FOXM1 also upregulates the expression of the antiapoptotic protein Survivin, which has been linked to TMZ resistance [61]. Collectively, concurrent treatment with thiostrepton or bortezomib and TMZ restores TMZ sensitivity and intensifies its apoptotic activity.

2.2. Combination with Topoisomerase II Inhibitors

Anthracyclines inhibit the topoisomerase II enzyme, intercalate between DNA bases, and cleave DNA into fragments. The accumulation of double-strand DNA breaks overwhelms the DNA repair response and drives the cells into apoptosis [64]. In anthracycline-resistant breast cancer cells, FOXM1 is highly upregulated [65]. FOXM1 overexpression is associated with an increase in DNA damage response proteins such as ATM and NBS1 [66][67]. It is also associated with the upregulation of antiapoptotic genes such as XIAP and Survivin [68]. Ghandhariyoun et al. demonstrated that FOXM1 aptamer enhanced doxorubicin-induced apoptosis in breast cancer cells and mouse xenografts [69]. Furthermore, thiostrepton increased doxorubicin accumulation in Jurkat cells due to the suppression of glutathione S-transferase pi (GSTpi) expression, a known culprit in multidrug resistance [70].

2.3. Combination with Mitotic Spindle Inhibitors

a. Vinca alkaloids: Vincristine, vinblastine, and vinorelbine are tubulin inhibitors. They inhibit microtubule formation and lead to cell cycle arrest at mitosis. Donovan et al. demonstrated that the combination therapy of RCM-1 and VCR exhibited superior anti-tumor activity in contrast to single-agent therapy. The authors explored using a lower VCR dose to limit VCR-induced neuropathy and liver dysfunction while maintaining anti-tumor activity in rhabdomyosarcoma cell lines and mouse xenografts [50]. Interestingly, RCM-1 can be injected intravenously using tumor-specific nanoparticles. Nanoparticle-based drug delivery enables more targeted and effective drug delivery and opens the door for anti-cancer combination therapies in a single infusion [50]. Researchers previously showed that RCM1 treatment increases the duration of mitosis in tumor cells [47], rationalizing the use of RCM1 with mitotic inhibitors to increase the efficacy of anti-cancer therapy.
b. Taxanes: Paclitaxel and docetaxel are similar to vinca alkaloids in that they inhibit tubulin and induce mitosis arrest. FOXM1 has an essential role in mitotic spindle formation, chromosome alignment, segregation, and daughter cell formation. Depletion of FOXM1 by thiostrepton (TST) downregulates the expression of the kinesin protein KIF20A, mediating mitotic spindle dysfunction and cellular senescence [54]. In pancreatic cancer cells, TST inhibits the prohibin1 protein, decreasing the phosphorylated ERK1/2 level, and decreases the expression of the ABC drug transporter, fostering a higher intracellular anti-cancer drug concentration [71]. Hence, TST synergizes with microtubule inhibitors, such as paclitaxel, to overcome drug resistance and induce mitotic catastrophe [71][72].

2.4. Combination with Antimetabolites

The antimetabolite family represents a large group of anti-cancer therapies, including folic acid antagonists and purine and pyrimidine analogs. They disturb DNA synthesis through the inhibition of key molecules in DNA’s structure.
a. Fluorouracil (5-FU) is a pyrimidine analog that blocks DNA synthesis through the suppression of the thymidylate synthase enzyme (TYMS) and the depletion of thymidine triphosphate. 5-FU is commonly used in adult solid tumors, including pancreatic and colon cancers. 5-FU-resistant colon cancer and cholangiocarcinoma cells exhibit high levels of FOXM1 and TYMS [73][74]. Moreover, FOXM1 binds directly into the TYMS promotor region and induces its expression [73]. Hence, FOXM1 overexpression mediates 5-FU resistance because of the increase in drug targets [73]. In addition, FOXM1 overexpression induces ABCC10 expression and increases drug efflux, promoting 5-FU resistance because of the decrease in the intracellular drug level [75]. FOXM1 inhibitors, in combination with 5-FU, reduce colony formation, decrease cancer cell migration, and induce caspase-dependent apoptosis in colon and cholangiocarcinoma cancer cell lines [73][74].
b. Cytarabine is another pyrimidine analog used mainly in hematologic malignancies such as acute myeloid leukemia (AML). Cytarabine and anthracycline are the standard treatments for pediatric patients and medically fit adults with AML. Patients requiring more than one cycle of chemotherapy to achieve disease remission had worse survival outcomes [76]. Chemotherapy resistance correlated with higher nuclear FOXM1 expression in post-treatment bone marrow samples [76]. FOXM-1-overexpressed AML cells were resistant to standard chemotherapy in both in vitro and AML mouse models. Also, FOXM1 inhibition re-sensitizes resistant AML cells to cytarabine therapy. As a result, FOXM1 inhibitors can be studied concurrently or before standard AML chemotherapy to enhance treatment efficacy and restore drug sensitivity [76]

References

  1. Clark, K.L.; Halay, E.D.; Lai, E.; Burley, S.K. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature 1993, 364, 412–420.
  2. Clevidence, D.E.; Overdier, D.G.; Tao, W.; Qian, X.; Pani, L.; Lai, E.; Costa, R.H. Identification of nine tissue-specific transcription factors of the hepatocyte nuclear factor 3/forkhead DNA-binding-domain family. Proc. Natl. Acad. Sci. USA 1993, 90, 3948–3952.
  3. Kaestner, K.H.; Lee, K.H.; Schlondorff, J.; Hiemisch, H.; Monaghan, A.P.; Schutz, G. Six members of the mouse forkhead gene family are developmentally regulated. Proc. Natl. Acad. Sci. USA 1993, 90, 7628–7631.
  4. Kalin, T.V.; Ustiyan, V.; Kalinichenko, V.V. Multiple faces of FoxM1 transcription factor: Lessons from transgenic mouse models. Cell Cycle 2011, 10, 396–405.
  5. Kim, I.M.; Ramakrishna, S.; Gusarova, G.A.; Yoder, H.M.; Costa, R.H.; Kalinichenko, V.V. The forkhead box m1 transcription factor is essential for embryonic development of pulmonary vasculature. J. Biol. Chem. 2005, 280, 22278–22286.
  6. Kalin, T.V.; Wang, I.C.; Meliton, L.; Zhang, Y.; Wert, S.E.; Ren, X.; Snyder, J.; Bell, S.M.; Graf, L., Jr.; Whitsett, J.A.; et al. Forkhead Box m1 transcription factor is required for perinatal lung function. Proc. Natl. Acad. Sci. USA 2008, 105, 19330–19335.
  7. Ustiyan, V.; Zhang, Y.; Perl, A.K.; Whitsett, J.A.; Kalin, T.V.; Kalinichenko, V.V. β-catenin and Kras/Foxm1 signaling pathway are critical to restrict Sox9 in basal cells during pulmonary branching morphogenesis. Dev. Dyn. 2016, 245, 590–604.
  8. Wang, I.C.; Meliton, L.; Ren, X.; Zhang, Y.; Balli, D.; Snyder, J.; Whitsett, J.A.; Kalinichenko, V.V.; Kalin, T.V. Deletion of Forkhead Box M1 transcription factor from respiratory epithelial cells inhibits pulmonary tumorigenesis. PLoS ONE 2009, 4, e6609.
  9. Bolte, C.; Zhang, Y.; Wang, I.C.; Kalin, T.V.; Molkentin, J.D.; Kalinichenko, V.V. Expression of Foxm1 transcription factor in cardiomyocytes is required for myocardial development. PLoS ONE 2011, 6, e22217.
  10. Bolte, C.; Zhang, Y.; York, A.; Kalin, T.V.; Schultz Jel, J.; Molkentin, J.D.; Kalinichenko, V.V. Postnatal ablation of Foxm1 from cardiomyocytes causes late onset cardiac hypertrophy and fibrosis without exacerbating pressure overload-induced cardiac remodeling. PLoS ONE 2012, 7, e48713.
  11. Gao, F.; Bian, F.; Ma, X.; Kalinichenko, V.V.; Das, S.K. Control of regional decidualization in implantation: Role of FoxM1 downstream of Hoxa10 and cyclin D3. Sci. Rep. 2015, 5, 13863.
  12. Wang, I.C.; Ustiyan, V.; Zhang, Y.; Cai, Y.; Kalin, T.V.; Kalinichenko, V.V. Foxm1 transcription factor is required for the initiation of lung tumorigenesis by oncogenic Kras(G12D.). Oncogene 2014, 33, 5391–5396.
  13. Ustiyan, V.; Wert, S.E.; Ikegami, M.; Wang, I.C.; Kalin, T.V.; Whitsett, J.A.; Kalinichenko, V.V. Foxm1 transcription factor is critical for proliferation and differentiation of Clara cells during development of conducting airways. Dev. Biol. 2012, 370, 198–212.
  14. Bolte, C.; Ustiyan, V.; Ren, X.; Dunn, A.W.; Pradhan, A.; Wang, G.; Kolesnichenko, O.A.; Deng, Z.; Zhang, Y.; Shi, D.; et al. Nanoparticle Delivery of Proangiogenic Transcription Factors into the Neonatal Circulation Inhibits Alveolar Simplification Caused by Hyperoxia. Am. J. Respir. Crit. Care Med. 2020, 202, 100–111.
  15. Cheng, X.H.; Black, M.; Ustiyan, V.; Le, T.; Fulford, L.; Sridharan, A.; Medvedovic, M.; Kalinichenko, V.V.; Whitsett, J.A.; Kalin, T.V. SPDEF inhibits prostate carcinogenesis by disrupting a positive feedback loop in regulation of the Foxm1 oncogene. PLoS Genet. 2014, 10, e1004656.
  16. Wang, I.C.; Snyder, J.; Zhang, Y.; Lander, J.; Nakafuku, Y.; Lin, J.; Chen, G.; Kalin, T.V.; Whitsett, J.A.; Kalinichenko, V.V. Foxm1 mediates cross talk between Kras/mitogen-activated protein kinase and canonical Wnt pathways during development of respiratory epithelium. Mol. Cell Biol. 2012, 32, 3838–3850.
  17. Wang, I.C.; Zhang, Y.; Snyder, J.; Sutherland, M.J.; Burhans, M.S.; Shannon, J.M.; Park, H.J.; Whitsett, J.A.; Kalinichenko, V.V. Increased expression of FoxM1 transcription factor in respiratory epithelium inhibits lung sacculation and causes Clara cell hyperplasia. Dev. Biol. 2010, 347, 301–314.
  18. Ribeiro, R.; Macedo, J.C.; Costa, M.; Ustiyan, V.; Shindyapina, A.V.; Tyshkovskiy, A.; Gomes, R.N.; Castro, J.P.; Kalin, T.V.; Vasques-Nóvoa, F.; et al. In vivo cyclic induction of the FOXM1 transcription factor delays natural and progeroid aging phenotypes and extends healthspan. Nat. Aging 2022, 2, 397–411.
  19. Black, M.; Arumugam, P.; Shukla, S.; Pradhan, A.; Ustiyan, V.; Milewski, D.; Kalinichenko, V.V.; Kalin, T.V. FOXM1 nuclear transcription factor translocates into mitochondria and inhibits oxidative phosphorylation. Mol. Biol. Cell 2020, 31, 1411–1424.
  20. Goda, C.; Balli, D.; Black, M.; Milewski, D.; Le, T.; Ustiyan, V.; Ren, X.; Kalinichenko, V.V.; Kalin, T.V. Loss of FOXM1 in macrophages promotes pulmonary fibrosis by activating p38 MAPK signaling pathway. PLoS Genet. 2020, 16, e1008692.
  21. Hasegawa, T.; Kikuta, J.; Sudo, T.; Matsuura, Y.; Matsui, T.; Simmons, S.; Ebina, K.; Hirao, M.; Okuzaki, D.; Yoshida, Y.; et al. Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1. Nat. Immunol. 2019, 20, 1631–1643.
  22. Kurahashi, T.; Yoshida, Y.; Ogura, S.; Egawa, M.; Furuta, K.; Hikita, H.; Kodama, T.; Sakamori, R.; Kiso, S.; Kamada, Y.; et al. Forkhead Box M1 Transcription Factor Drives Liver Inflammation Linking to Hepatocarcinogenesis in Mice. Cell Mol. Gastroenterol. Hepatol. 2020, 9, 425–446.
  23. Xia, H.; Ren, X.; Bolte, C.S.; Ustiyan, V.; Zhang, Y.; Shah, T.A.; Kalin, T.V.; Whitsett, J.A.; Kalinichenko, V.V. Foxm1 regulates resolution of hyperoxic lung injury in newborns. Am. J. Respir. Cell Mol. Biol. 2015, 52, 611–621.
  24. Balli, D.; Ren, X.; Chou, F.S.; Cross, E.; Zhang, Y.; Kalinichenko, V.V.; Kalin, T.V. Foxm1 transcription factor is required for macrophage migration during lung inflammation and tumor formation. Oncogene 2012, 31, 3875–3888.
  25. Ren, X.; Zhang, Y.; Snyder, J.; Cross, E.R.; Shah, T.A.; Kalin, T.V.; Kalinichenko, V.V. Forkhead box M1 transcription factor is required for macrophage recruitment during liver repair. Mol. Cell Biol. 2010, 30, 5381–5393.
  26. Barger, C.J.; Branick, C.; Chee, L.; Karpf, A.R. Pan-Cancer Analyses Reveal Genomic Features of FOXM1 Overexpression in Cancer. Cancers 2019, 11, 251.
  27. Korver, W.; Roose, J.; Heinen, K.; Weghuis, D.O.; de Bruijn, D.; van Kessel, A.G.; Clevers, H. The human TRIDENT/HFH-11/FKHL16 gene: Structure, localization, and promoter characterization. Genomics 1997, 46, 435–442.
  28. Jiang, M.; Li, M.; Fu, X.; Huang, Y.; Qian, H.; Sun, R.; Mao, Y.; Xie, Y.; Li, Y. Simultaneously detection of genomic and expression alterations in prostate cancer using cDNA microarray. Prostate 2008, 68, 1496–1509.
  29. Lensch, R.; Gotz, C.; Andres, C.; Bex, A.; Lehmann, J.; Zwergel, T.; Unteregger, G.; Kamradt, J.; Stoeckle, M.; Wullich, B. Comprehensive genotypic analysis of human prostate cancer cell lines and sublines derived from metastases after orthotopic implantation in nude mice. Int. J. Oncol. 2002, 21, 695–706.
  30. Spirin, K.S.; Simpson, J.F.; Takeuchi, S.; Kawamata, N.; Miller, C.W.; Koeffler, H.P. p27/Kip1 mutation found in breast cancer. Cancer Res. 1996, 56, 2400–2404.
  31. Singh, B.; Gogineni, S.K.; Sacks, P.G.; Shaha, A.R.; Shah, J.P.; Stoffel, A.; Rao, P.H. Molecular cytogenetic characterization of head and neck squamous cell carcinoma and refinement of 3q amplification. Cancer Res. 2001, 61, 4506–4513.
  32. Rodriguez, S.; Khabir, A.; Keryer, C.; Perrot, C.; Drira, M.; Ghorbel, A.; Jlidi, R.; Bernheim, A.; Valent, A.; Busson, P. Conventional and array-based comparative genomic hybridization analysis of nasopharyngeal carcinomas from the Mediterranean area. Cancer Genet. Cytogenet. 2005, 157, 140–147.
  33. Heselmeyer, K.; Macville, M.; Schrock, E.; Blegen, H.; Hellstrom, A.C.; Shah, K.; Auer, G.; Ried, T. Advanced-stage cervical carcinomas are defined by a recurrent pattern of chromosomal aberrations revealing high genetic instability and a consistent gain of chromosome arm 3q. Genes. Chromosomes Cancer 1997, 19, 233–240.
  34. Kelleher, F.C.; O’Sullivan, H. FOXM1 in sarcoma: Role in cell cycle, pluripotency genes and stem cell pathways. Oncotarget 2016, 7, 42792–42804.
  35. Liao, G.-B.; Li, X.-Z.; Zeng, S.; Liu, C.; Yang, S.-M.; Yang, L.; Hu, C.-J.; Bai, J.-Y. Regulation of the master regulator FOXM1 in cancer. Cell Commun. Signal 2018, 16, 57.
  36. Nandi, D.; Cheema, P.S.; Jaiswal, N.; Nag, A. FoxM1: Repurposing an oncogene as a biomarker. Semin. Cancer Biol. 2018, 52, 74–84.
  37. Kalinichenko, V.V.; Kalin, T.V. Is there potential to target FOXM1 for ‘undruggable’ lung cancers? Expert. Opin. Ther. Targets 2015, 19, 865–867.
  38. Halasi, M.; Hitchinson, B.; Shah, B.N.; Váraljai, R.; Khan, I.; Benevolenskaya, E.V.; Gaponenko, V.; Arbiser, J.L.; Gartel, A.L. Honokiol is a FOXM1 antagonist. Cell Death Dis. 2018, 9, 84.
  39. Zhang, J.R.; Lu, F.; Lu, T.; Dong, W.H.; Li, P.; Liu, N.; Ma, D.X.; Ji, C.Y. Inactivation of FoxM1 transcription factor contributes to curcumin-induced inhibition of survival, angiogenesis, and chemosensitivity in acute myeloid leukemia cells. J. Mol. Med. 2014, 92, 1319–1330.
  40. Wu, Y.H.; Chiu, W.T.; Young, M.J.; Chang, T.H.; Huang, Y.F.; Chou, C.Y. Solanum Incanum Extract Downregulates Aldehyde Dehydrogenase 1-Mediated Stemness and Inhibits Tumor Formation in Ovarian Cancer Cells. J. Cancer 2015, 6, 1011–1019.
  41. Tian, T.; Li, J.; Li, B.; Wang, Y.; Li, M.; Ma, D.; Wang, X. Genistein exhibits anti-cancer effects via down-regulating FoxM1 in H446 small-cell lung cancer cells. Tumour Biol. 2014, 35, 4137–4145.
  42. Dong, G.Z.; Jeong, J.H.; Lee, Y.I.; Lee, S.Y.; Zhao, H.Y.; Jeon, R.; Lee, H.J.; Ryu, J.H. Diarylheptanoids suppress proliferation of pancreatic cancer PANC-1 cells through modulating shh-Gli-FoxM1 pathway. Arch. Pharm. Res. 2017, 40, 509–517.
  43. Bhat, U.G.; Halasi, M.; Gartel, A.L. Thiazole antibiotics target FoxM1 and induce apoptosis in human cancer cells. PLoS ONE 2009, 4, e5592.
  44. Bhat, U.G.; Halasi, M.; Gartel, A.L. FoxM1 is a general target for proteasome inhibitors. PLoS ONE 2009, 4, e6593.
  45. Borhani, S.; Gartel, A.L. FOXM1: A potential therapeutic target in human solid cancers. Expert. Opin. Ther. Targets 2020, 24, 205–217.
  46. Sun, L.; Ren, X.; Wang, I.-C.; Pradhan, A.; Zhang, Y.; Flood, H.M.; Han, B.; Whitsett, J.A.; Kalin, T.V.; Kalinichenko, V.V. The FOXM1 inhibitor RCM-1 suppresses goblet cell metaplasia and prevents IL-13 and STAT6 signaling in allergen-exposed mice. Sci. Signal. 2017, 10, eaai8583.
  47. Shukla, S.; Milewski, D.; Pradhan, A.; Rama, N.; Rice, K.; Le, T.; Flick, M.J.; Vaz, S.; Zhao, X.; Setchell, K.D.; et al. The FOXM1 Inhibitor RCM-1 Decreases Carcinogenesis and Nuclear β-Catenin. Mol. Cancer Ther. 2019, 18, 1217–1229.
  48. Chesnokov, M.S.; Halasi, M.; Borhani, S.; Arbieva, Z.; Shah, B.N.; Oerlemans, R.; Khan, I.; Camacho, C.J.; Gartel, A.L. Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cells. Cell Death Dis. 2021, 12, 704.
  49. Khan, I.; Kaempf, A.; Raghuwanshi, S.; Chesnokov, M.; Zhang, X.; Wang, Z.; Domling, A.; Tyner, J.W.; Camacho, C.; Gartel, A.L. Favorable outcomes of NPM1mut AML patients are due to transcriptional inactivation of FOXM1, presenting a new target to overcome chemoresistance. Blood Cancer J. 2023, 13, 128.
  50. Donovan, J.; Deng, Z.; Bian, F.; Shukla, S.; Gomez-Arroyo, J.; Shi, D.; Kalinichenko, V.V.; Kalin, T.V. Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma via the combination therapy with FOXM1 inhibitor RCM1. Front. Oncol. 2023, 13, 1112859.
  51. Gormally, M.V.; Dexheimer, T.S.; Marsico, G.; Sanders, D.A.; Lowe, C.; Matak-Vinković, D.; Michael, S.; Jadhav, A.; Rai, G.; Maloney, D.J.; et al. Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition. Nat. Commun. 2014, 5, 5165.
  52. Zhang, Z.; Xue, S.-T.; Gao, Y.; Li, Y.; Zhou, Z.; Wang, J.; Li, Z.; Liu, Z. Small molecule targeting FOXM1 DNA binding domain exhibits anti-tumor activity in ovarian cancer. Cell Death Discov. 2022, 8, 280.
  53. Nestal de Moraes, G.; Bella, L.; Zona, S.; Burton, M.J.; Lam, E.W. Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance. Curr. Drug Targets 2016, 17, 164–177.
  54. Yao, S.; Fan, L.Y.; Lam, E.W. The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance. Semin. Cancer Biol. 2018, 50, 77–89.
  55. Laoukili, J.; Kooistra, M.R.; Brás, A.; Kauw, J.; Kerkhoven, R.M.; Morrison, A.; Clevers, H.; Medema, R.H. FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat. Cell Biol. 2005, 7, 126–136.
  56. Replogle, J.M.; Zhou, W.; Amaro, A.E.; McFarland, J.M.; Villalobos-Ortiz, M.; Ryan, J.; Letai, A.; Yilmaz, O.; Sheltzer, J.; Lippard, S.J.; et al. Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division. Proc. Natl. Acad. Sci. USA 2020, 117, 30566–30576.
  57. Ippolito, M.R.; Martis, V.; Hong, C.; Wardenaar, R.; Zerbib, J.; Spierings, D.C.J.; Ben-David, U.; Foijer, F.; Santaguida, S. Aneuploidy-driven genome instability triggers resistance to chemotherapy. bioRxiv 2020.
  58. Chiu, W.T.; Huang, Y.F.; Tsai, H.Y.; Chen, C.C.; Chang, C.H.; Huang, S.C.; Hsu, K.F.; Chou, C.Y. FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells. Oncotarget 2015, 6, 2349–2365.
  59. Choi, H.S.; Kim, Y.K.; Hwang, K.G.; Yun, P.Y. Increased FOXM1 Expression by Cisplatin Inhibits Paclitaxel-Related Apoptosis in Cisplatin-Resistant Human Oral Squamous Cell Carcinoma (OSCC) Cell Lines. Int. J. Mol. Sci. 2020, 21, 8897.
  60. Zhou, J.; Wang, Y.; Wang, Y.; Yin, X.; He, Y.; Chen, L.; Wang, W.; Liu, T.; Di, W. FOXM1 modulates cisplatin sensitivity by regulating EXO1 in ovarian cancer. PLoS ONE 2014, 9, e96989.
  61. Tang, J.H.; Yang, L.; Chen, J.X.; Li, Q.R.; Zhu, L.R.; Xu, Q.F.; Huang, G.H.; Zhang, Z.X.; Xiang, Y.; Du, L.; et al. Bortezomib inhibits growth and sensitizes glioma to temozolomide (TMZ) via down-regulating the FOXM1-Survivin axis. Cancer Commun. 2019, 39, 81.
  62. Zhang, N.; Wu, X.; Yang, L.; Xiao, F.; Zhang, H.; Zhou, A.; Huang, Z.; Huang, S. FoxM1 inhibition sensitizes resistant glioblastoma cells to temozolomide by downregulating the expression of DNA-repair gene Rad51. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2012, 18, 5961–5971.
  63. Peng, W.X.; Han, X.; Zhang, C.L.; Ge, L.; Du, F.Y.; Jin, J.; Gong, A.H. FoxM1-mediated RFC5 expression promotes temozolomide resistance. Cell Biol. Toxicol. 2017, 33, 527–537.
  64. Yang, F.; Kemp, C.J.; Henikoff, S. Anthracyclines induce double-strand DNA breaks at active gene promoters. Mutat. Res. 2015, 773, 9–15.
  65. Khongkow, M.; Olmos, Y.; Gong, C.; Gomes, A.R.; Monteiro, L.J.; Yagüe, E.; Cavaco, T.B.; Khongkow, P.; Man, E.P.; Laohasinnarong, S.; et al. SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer. Carcinogenesis 2013, 34, 1476–1486.
  66. Millour, J.; de Olano, N.; Horimoto, Y.; Monteiro, L.J.; Langer, J.K.; Aligue, R.; Hajji, N.; Lam, E.W. ATM and p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance. Mol. Cancer Ther. 2011, 10, 1046–1058.
  67. Khongkow, P.; Karunarathna, U.; Khongkow, M.; Gong, C.; Gomes, A.R.; Yagüe, E.; Monteiro, L.J.; Kongsema, M.; Zona, S.; Man, E.P.; et al. FOXM1 targets NBS1 to regulate DNA damage-induced senescence and epirubicin resistance. Oncogene 2014, 33, 4144–4155.
  68. Nestal de Moraes, G.; Delbue, D.; Silva, K.L.; Robaina, M.C.; Khongkow, P.; Gomes, A.R.; Zona, S.; Crocamo, S.; Mencalha, A.L.; Magalhães, L.M.; et al. FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance. Cell Signal 2015, 27, 2496–2505.
  69. Ghandhariyoun, N.; Jaafari, M.R.; Nikoofal-Sahlabadi, S.; Taghdisi, S.M.; Moosavian, S.A. Reducing Doxorubicin resistance in breast cancer by liposomal FOXM1 aptamer: In vitro and in vivo. Life Sci. 2020, 262, 118520.
  70. Wang, J.Y.; Jia, X.H.; Xing, H.Y.; Li, Y.J.; Fan, W.W.; Li, N.; Xie, S.Y. Inhibition of Forkhead box protein M1 by thiostrepton increases chemosensitivity to doxorubicin in T-cell acute lymphoblastic leukemia. Mol. Med. Rep. 2015, 12, 1457–1464.
  71. Huang, C.; Zhang, X.; Jiang, L.; Zhang, L.; Xiang, M.; Ren, H. FoxM1 Induced Paclitaxel Resistance via Activation of the FoxM1/PHB1/RAF-MEK-ERK Pathway and Enhancement of the ABCA2 Transporter. Mol. Ther. Oncolytics 2019, 14, 196–212.
  72. Westhoff, G.L.; Chen, Y.; Teng, N.N.H. Targeting FOXM1 Improves Cytotoxicity of Paclitaxel and Cisplatinum in Platinum-Resistant Ovarian Cancer. Int. J. Gynecol. Cancer 2017, 27, 1602–1609.
  73. Varghese, V.; Magnani, L.; Harada-Shoji, N.; Mauri, F.; Szydlo, R.M.; Yao, S.; Lam, E.W.; Kenny, L.M. FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression. Sci. Rep. 2019, 9, 1505.
  74. Klinhom-On, N.; Seubwai, W.; Sawanyawisuth, K.; Obchoei, S.; Mahalapbutr, P.; Wongkham, S. FOXM1 inhibitor, Siomycin A, synergizes and restores 5-FU cytotoxicity in human cholangiocarcinoma cell lines via targeting thymidylate synthase. Life Sci. 2021, 286, 120072.
  75. Xie, T.; Geng, J.; Wang, Y.; Wang, L.; Huang, M.; Chen, J.; Zhang, K.; Xue, L.; Liu, X.; Mao, X.; et al. FOXM1 evokes 5-fluorouracil resistance in colorectal cancer depending on ABCC10. Oncotarget 2017, 8, 8574–8589.
  76. Khan, I.; Halasi, M.; Patel, A.; Schultz, R.; Kalakota, N.; Chen, Y.H.; Aardsma, N.; Liu, L.; Crispino, J.D.; Mahmud, N.; et al. FOXM1 contributes to treatment failure in acute myeloid leukemia. JCI Insight 2018, 3, e121583.
More
Information
Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , , , ,
View Times: 47
Revisions: 2 times (View History)
Update Date: 05 Mar 2024
1000/1000