Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

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doi: 10.17219/acem/161165

Publication type: review

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Lewandowski D, Szewczyk A, Radzka J, et al. The natural origins of cytostatic compounds used in rhabdomyosarcoma therapy [published online as ahead of print on March 15, 2023]. Adv Clin Exp Med. 2023. doi:10.17219/acem/161165

The natural origins of cytostatic compounds used in rhabdomyosarcoma therapy

Damian Lewandowski1,A,B,C,D,E,F, Anna Szewczyk2,B,C,D,F, Justyna Radzka1,B,C,D,F, Magda Dubińska-Magiera1,A,B,C,D,E,F, Weronika Kazimierczak1,B,C,D,F, Małgorzata Daczewska1,A,B,C,D,E,F, Marta Migocka-Patrzałek1,A,B,C,D,E,F

1 Department of Animal Developmental Biology, Faculty of Biological Sciences, University of Wrocław, Poland

2 Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Poland


Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and represents a high-grade neoplasm of skeletal myoblast-like cells. About 40% of all registered soft tissue tumors are RMSs. This paper describes our current understanding of the RMS subtypes (alveolar (ARMS), embryonic (ERMS), pleomorphic (PRMS), and spindle cell/sclerosing (s/scRMS)), diagnostic methods, molecular bases, and characteristics. We also present the currently used treatment methods and the potential use of natural substances in the treatment of this type of cancer. Natural cytotoxic substances are compounds that have been the subject of numerous studies and discussions in recent years. Since anti-cancer therapies are often limited by a low therapeutic index and cancer resistance to pharmacotherapy, it is very important to search for new, effective compounds. Additionally, compounds of a natural origin are usually readily available and have a reduced cytotoxicity. Thus, the undiscovered potential of natural anti-cancer compounds makes this field of research a very important area. The introduction of model species into research examining the use of natural cytostatic therapies for RMS will allow for further assessment of the effects of these compounds on cancerous and healthy tissues.

Key words

rhabdomyosarcoma, natural compounds, anti-cancer therapy, muscle cells

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References (149)

  1. Arndt CAS, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med. 1999;341(5):342–352. doi:10.1056/NEJM199907293410507
  2. Ries L, Smith M, Gurney J, et al., eds. Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975–1995. Bethesda, USA: National Cancer Institute, SEER Program. NIH Pub. No. 99-4649. Accessed November 10, 2022.
  3. Skubitz KM, D’Adamo DR. Sarcoma. Mayo Clin Proc. 2007;82(11):1409–1432. doi:10.4065/82.11.1409
  4. Hoang NT, Acevedo LA, Mann MJ, Tolani B. A review of soft-tissue sarcomas: Translation of biological advances into treatment measures. Cancer Manag Res. 2018;10:1089–1114. doi:10.2147/CMAR.S159641
  5. Ognjanovic S, Linabery AM, Charbonneau B, Ross JA. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–2005. Cancer. 2009;115(18):4218–4226. doi:10.1002/cncr.24465
  6. Dasgupta R, Fuchs J, Rodeberg D. Rhabdomyosarcoma. Semin Pediatr Surg. 2016;25(5):276–283. doi:10.1053/j.sempedsurg.2016.09.011
  7. Ingley KM, Cohen-Gogo S, Gupta AA. Systemic therapy in pediatric-type soft-tissue sarcoma. Curr Oncol. 2020;27(11):6–16. doi:10.3747/co.27.5481
  8. Hustu HO, Pinkei D, Pratt CB. Treatment of clinically localized Ewing’s sarcoma with radiotherapy and combination chemotherapy. Cancer. 1972;30(6):1522–1527. doi:10.1002/1097-0142(197212)30:6<1522::AID-CNCR2820300617>3.0.CO;2-J
  9. Skapek SX, Ferrari A, Gupta AA, et al. Rhabdomyosarcoma. Nat Rev Dis Primers. 2019;5(1):1. doi:10.1038/s41572-018-0051-2
  10. Martin-Giacalone BA, Weinstein PA, Plon SE, Lupo PJ. Pediatric rhabdomyosarcoma: Epidemiology and genetic susceptibility. J Clin Med. 2021;10(9):2028. doi:10.3390/jcm10092028
  11. Barr FG, Qualman SJ, Macris MH, et al. Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Cancer Res. 2002;62(16):4704–4710. PMID:12183429.
  12. Shern JF, Selfe J, Izquierdo E, et al. Genomic classification and clinical outcome in rhabdomyosarcoma: A report from an international consortium. J Clin Oncol. 2021;39(26):2859–2871. doi:10.1200/JCO.20.03060
  13. Panda SP, Chinnaswamy G, Vora T, et al. Diagnosis and management of rhabdomyosarcoma in children and adolescents: ICMR Consensus Document. Indian J Pediatr. 2017;84(5):393–402. doi:10.1007/s12098-017-2315-3
  14. Dias P, Chen B, Dilday B, et al. Strong immunostaining for myogenin in rhabdomyosarcoma is significantly associated with tumors of the alveolar subclass. Am J Pathol. 2000;156(2):399–408. doi:10.1016/S0002-9440(10)64743-8
  15. Ilanthodi S, Pallipady A, Jayaprakash K, Monteiro F. Secondary cardiac pleomorphic rhabdomyosarcoma: A case report and review of literature. J Clin Diagn Res. 2011;5(2):364–366. Accessed November 10, 2022.
  16. Yin J, Liu Z, Yang K. Pleomorphic rhabdomyosarcoma of the liver with a hepatic cyst in an adult: Case report and literature review. Medicine (Baltimore). 2018;97(29):e11335. doi:10.1097/MD.0000000000011335
  17. Shirafkan A, Boroumand N, Komak S, Duchini A, Cicalese L. Pancreatic pleomorphic rhabdomyosarcoma. Int J Sur Case Rep. 2015;13:33–36. doi:10.1016/j.ijscr.2015.05.029
  18. Alaggio R, Zhang L, Sung YS, et al. A molecular study of pediatric spindle and sclerosing rhabdomyosarcoma: Identification of novel and recurrent VGLL2-related fusions in infantile cases. Am J Surg Pathol. 2016;40(2):224–235. doi:10.1097/PAS.0000000000000538
  19. Smith MH, Atherton D, Reith JD, Islam NM, Bhattacharyya I, Cohen DM. Rhabdomyosarcoma, spindle cell/sclerosing variant: A clinical and histopathological examination of this rare variant with three new cases from the oral cavity. Head Neck Pathol. 2017;11(4):494–500. doi:10.1007/s12105-017-0818-x
  20. Rudzinski ER, Anderson JR, Hawkins DS, Skapek SX, Parham DM, Teot LA. The World Health Organization Classification of Skeletal Muscle Tumors in Pediatric Rhabdomyosarcoma: A report from the Children’s Oncology Group. Arch Pathol Lab Med. 2015;139(10):1281–1287. doi:10.5858/arpa.2014-0475-OA
  21. Williams LA, Richardson M, Kehm RD, et al. The association between sex and most childhood cancers is not mediated by birthweight. Cancer Epidemiol. 2018;57:7–12. doi:10.1016/j.canep.2018.09.002
  22. Dorak MT, Karpuzoglu E. Gender differences in cancer susceptibility: An inadequately addressed issue. Front Genet. 2012;3:268. doi:10.3389/fgene.2012.00268
  23. van Erp AEM, Versleijen-Jonkers YMH, van der Graaf WTA, Fleuren EDG. Targeted therapy-based combination treatment in rhabdomyosarcoma. Mol Cancer Ther. 2018;17(7):1365–1380. doi:10.1158/1535-7163.MCT-17-1131
  24. Schlessinger J. Receptor tyrosine kinases: Legacy of the first two decades. Cold Spring Harb Perspect Biol. 2014;6(3):a008912. doi:10.1101/cshperspect.a008912
  25. Temin HM. Studies on carcinogenesis by avian sarcoma viruses. V. Requirement for new DNA synthesis and for cell division. J Cell Physiol. 1967;69(1):53–63. doi:10.1002/jcp.1040690108
  26. El-Badry OM, Minniti C, Kohn EC, Houghton PJ, Daughaday WH, Helman LJ. Insulin-like growth factor II acts as an autocrine growth and motility factor in human rhabdomyosarcoma tumors. Cell Growth Differ. 1990;1(7):325–331. PMID:2177632.
  27. Wang Q, Wu Y, Aerts T, Slegers H, Clauwaert J. Expression of IGF-I and IGF-II receptors in rat C6 glioma cells as a function of the growth phase. Cell Physiol Biochem. 1998;8(6):304–313. doi:10.1159/000016292
  28. Blandford MC, Barr FG, Lynch JC, Randall RL, Qualman SJ, Keller C. Rhabdomyosarcomas utilize developmental, myogenic growth factors for disease advantage: A report from the children’s oncology group. Pediatr Blood Cancer. 2006;46(3):329–338. doi:10.1002/pbc.20466
  29. Makawita S, Ho M, Durbin AD, Thorner PS, Malkin D, Somers GR. Expression of insulin-like growth factor pathway proteins in rhabdomyosarcoma: IGF-2 expression is associated with translocation-negative tumors. Pediatr Dev Pathol. 2009;12(2):127–135. doi:10.2350/08-05-0477.1
  30. Rikhof B, de Jong S, Suurmeijer AJ, Meijer C, van der Graaf WT. The insulin-like growth factor system and sarcomas. J Pathol. 2009;217(4):469–482. doi:10.1002/path.2499
  31. Martins AS, Olmos D, Missiaglia E, Shipley J. Targeting the insulin-like growth factor pathway in rhabdomyosarcomas: Rationale and future perspectives. Sarcoma. 2011;2011:209736. doi:10.1155/2011/209736
  32. Fuss E. Lignans in plant cell and organ cultures: An overview. Phytochem Rev. 2003;2(3):307–320. doi:10.1023/B:PHYT.0000045500.56476.f5
  33. Vasilcanu D, Girnita A, Girnita L, Vasilcanu R, Axelson M, Larsson O. The cyclolignan PPP induces activation loop-specific inhibition of tyrosine phosphorylation of the insulin-like growth factor-1 receptor: Link to the phosphatidyl inositol-3 kinase/Akt apoptotic pathway. Oncogene. 2004;23(47):7854–7862. doi:10.1038/sj.onc.1208065
  34. Tarnowski M, Tkacz M, Zgutka K, Bujak J, Kopytko P, Pawlik A. Picropodophyllin (PPP) is a potent rhabdomyosarcoma growth inhibitor both in vitro and in vivo. BMC Cancer. 2017;17(1):532. doi:10.1186/s12885-017-3495-y
  35. Bagatell R, Norris R, Ingle AM, et al. Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: A children’s oncology group study. Pediatr Blood Cancer. 2014;61(5):833–839. doi:10.1002/pbc.24874
  36. van de Velde ME, Kaspers GL, Abbink FCH, Wilhelm AJ, Ket JCF, van den Berg MH. Vincristine-induced peripheral neuropathy in children with cancer: A systematic review. Crit Rev Oncol Hematol. 2017;114:114–130. doi:10.1016/j.critrevonc.2017.04.004
  37. Morgenstern DA, Rees H, Sebire NJ, Shipley J, Anderson J. Rhabdomyosarcoma subtyping by immunohistochemical assessment of myogenin: Tissue array study and review of the literature. Pathol Oncol Res. 2008;14(3):233–238. doi:10.1007/s12253-008-9012-5
  38. Ramadan F, Fahs A, Ghayad SE, Saab R. Signaling pathways in rhabdomyosarcoma invasion and metastasis. Cancer Metastasis Rev. 2020;39(1):287–301. doi:10.1007/s10555-020-09860-3
  39. Anderson JL, Park A, Akiyama R, Tap WD, Denny CT, Federman N. Evaluation of in vitro activity of the class I PI3K inhibitor buparlisib (BKM120) in pediatric bone and soft tissue sarcomas. PLoS One. 2015;10(9):e0133610. doi:10.1371/journal.pone.0133610
  40. Guenther MK, Graab U, Fulda S. Synthetic lethal interaction between PI3K/Akt/mTOR and Ras/MEK/ERK pathway inhibition in rhabdomyosarcoma. Cancer Lett. 2013;337(2):200–209. doi:10.1016/j.canlet.2013.05.010
  41. Renshaw J, Taylor KR, Bishop R, et al. Dual blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) pathways synergistically inhibits rhabdomyosarcoma cell growth in vitro and in vivo. Clin Cancer Res. 2013;19(21):5940–5951. doi:10.1158/1078-0432.CCR-13-0850
  42. Almazán-Moga A, Zarzosa P, Molist C, et al. Ligand-dependent Hedgehog pathway activation in rhabdomyosarcoma: The oncogenic role of the ligands. Br J Cancer. 2017;117(9):1314–1325. doi:10.1038/bjc.2017.305
  43. Ingham PW, McMahon AP. Hedgehog signaling in animal development: Paradigms and principles. Genes Dev. 2001;15(23):3059–3087. doi:10.1101/gad.938601
  44. Teglund S, Toftgård R. Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta Rev Cancer. 2010;1805(2):181–208. doi:10.1016/j.bbcan.2010.01.003
  45. Zibat A, Missiaglia E, Rosenberger A, et al. Activation of the Hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma. Oncogene. 2010;29(48):6323–6330. doi:10.1038/onc.2010.368
  46. Badagabettu S, Shetty P, D’Souza M. A unique variation of azygos system of veins. J Cardiovasc Echography. 2016;26(2):61–64. doi:10.4103/2211-4122.183761
  47. Crist W, Gehan EA, Ragab AH, et al. The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol. 1995;13(3):610–630. doi:10.1200/JCO.1995.13.3.610
  48. Srivastava RK, Kaylani SZ, Edrees N, et al. GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis. Oncotarget. 2014;5(23):12151–12165. doi:10.18632/oncotarget.2569
  49. Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009;8(7):547–566. doi:10.1038/nrd2907
  50. Francis AM, Alexander A, Liu Y, et al. CDK4/6 inhibitors sensitize Rb-positive sarcoma cells to Wee1 kinase inhibition through reversible cell-cycle arrest. Mol Cancer Ther. 2017;16(9):1751–1764. doi:10.1158/1535-7163.MCT-17-0040
  51. Montoya‐Cerrillo DM, Diaz‐Perez JA, Velez‐Torres JM, Montgomery EA, Rosenberg AE. Novel fusion genes in spindle cell rhabdomyosarcoma: The spectrum broadens. Genes Chromosomes Cancer. 2021;60(10):687–694. doi:10.1002/gcc.22978
  52. Hugle M, Belz K, Fulda S. Identification of synthetic lethality of PLK1 inhibition and microtubule-destabilizing drugs. Cell Death Differ. 2015;22(12):1946–1956. doi:10.1038/cdd.2015.59
  53. Rogojanu R, Thalhammer T, Thiem U, et al. Quantitative image analysis of epithelial and stromal area in histological sections of colorectal cancer: An emerging diagnostic tool. Biomed Res Int. 2015;2015:569071. doi:10.1155/2015/569071
  54. Scheinman MM, Morady F. Invasive cardiac electrophysiologic testing: The current state of the art. Circulation. 1983;67(6):1169–1173. doi:10.1161/01.cir.67.6.1169
  55. Kahen E, Yu D, Harrison DJ, et al. Identification of clinically achievable combination therapies in childhood rhabdomyosarcoma. Cancer Chemother Pharmacol. 2016;78(2):313–323. doi:10.1007/s00280-016-3077-8
  56. Stewart E, Federico SM, Chen X, et al. Orthotopic patient-derived xenografts of paediatric solid tumours. Nature. 2017;549(7670):96–100. doi:10.1038/nature23647
  57. Brandsma I, Fleuren EDG, Williamson CT, Lord CJ. Directing the use of DDR kinase inhibitors in cancer treatment. Exp Opin Investig Dugs. 2017;26(12):1341–1355. doi:10.1080/13543784.2017.1389895
  58. Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science. 2017;355(6330):1152–1158. doi:10.1126/science.aam7344
  59. Fam HK, Walton C, Mitra SA, et al. TDP1 and PARP1 deficiency are cytotoxic to rhabdomyosarcoma cells. Mol Cancer Res. 2013;11(10):1179–1192. doi:10.1158/1541-7786.MCR-12-0575
  60. Smith MA, Reynolds CP, Kang MH, et al. Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program. Clin Cancer Res. 2015;21(4):819–832. doi:10.1158/1078-0432.CCR-14-2572
  61. Basit F, Humphreys R, Fulda S. RIP1 protein-dependent assembly of a cytosolic cell death complex is required for inhibitor of apoptosis (IAP) inhibitor-mediated sensitization to lexatumumab-induced apoptosis. J Biol Chem. 2012;287(46):38767–38777. doi:10.1074/jbc.M112.398966
  62. Ueno M, Ikeda M, Morizane C, et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: A non-randomised, multicentre, open-label, phase 1 study. Lancet Gastroenterol Hepatol. 2019;4(8):611–621. doi:10.1016/S2468-1253(19)30086-X
  63. Dantonello TM, Int-Veen C, Schuck A, et al. Survival following disease recurrence of primary localized alveolar rhabdomyosarcoma. Pediatr Blood Cancer. 2013;60(8):1267–1273. doi:10.1002/pbc.24488
  64. Malempati S, Hawkins DS. Rhabdomyosarcoma: Review of the Children’s Oncology Group (COG) Soft-Tissue Sarcoma Committee experience and rationale for current COG studies. Pediatr Blood Cancer. 2012;59(1):5–10. doi:10.1002/pbc.24118
  65. Maurer HM, Crist W, Lawrence W, et al. The Intergroup Rhabdomyosarcoma Study I: A final report. Cancer. 1988;61(2):209–220. doi:10.1002/1097-0142(19880115)61:2<209::AID-CNCR2820610202>3.0.CO;2-L
  66. Maurer HM, Gehan EA, Beltangady M, et al. The Intergroup Rhabdomyosarcoma Study II: Objectives and study design. Cancer. 1993;71(5):1904–1922. doi:10.1002/1097-0142(19930301)71:5<1904::AID-CNCR2820710530>3.0.CO;2-X
  67. Bayoumy M, Wynn T, Jamil A, Kahwash S, Klopfenstein K, Ruymann F. Prenatal presentation supports the in utero development of congenital leukemia: A case report. J Pediatr Hematol Oncol. 2003;25(2):148–152. doi:10.1097/00043426-200302000-00013
  68. Najem S, Langemann D, Appl B, et al. Smac mimetic LCL161 supports neuroblastoma chemotherapy in a drug class-dependent manner and synergistically interacts with ALK inhibitor TAE684 in cells with ALK mutation F1174L. Oncotarget. 2016;7(45):72634–72653. doi:10.18632/oncotarget.12055
  69. Martino E, Casamassima G, Castiglione S, et al. Vinca alkaloids and analogues as anti-cancer agents: Looking back, peering ahead. Bioorg Med Chem Lett. 2018;28(17):2816–2826. doi:10.1016/j.bmcl.2018.06.044
  70. Avendaño C, Menéndez JC. Anticancer drugs acting via radical species, photosensitizers and photodynamic therapy of cancer. In: Medicinal Chemistry of Anticancer Drugs. Amsterdam, the Netherlands: Elsevier; 2008:93–138. doi:10.1016/B978-0-444-52824-7.00004-4
  71. Sobell HM. Actinomycin and DNA transcription. Proc Natl Acad Sci U S A. 1985;82(16):5328–5331. doi:10.1073/pnas.82.16.5328
  72. Koscielniak E, Harms D, Henze G, et al. Results of treatment for soft tissue sarcoma in childhood and adolescence: A final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86. J Clin Oncol. 1999;17(12):3706–3719. doi:10.1200/JCO.1999.17.12.3706
  73. Furlanut M, Franceschi L. Pharmacology of ifosfamide. Oncology. 2003;65(Suppl 2):2–6. doi:10.1159/000073350
  74. Kenney LB, Laufer MR, Grant FD, Grier H, Diller L. High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer. 2001;91(3):613–621. doi:10.1002/1097-0142(20010201)91:3<613::AID-CNCR1042>3.0.CO;2-R
  75. Eaton BR, McDonald MW, Kim S, et al. Radiation therapy target volume reduction in pediatric rhabdomyosarcoma: Implications for patterns of disease recurrence and overall survival. Cancer. 2013;119(8):1578–1585. doi:10.1002/cncr.27934
  76. Bisogno G, De Salvo GL, Bergeron C, et al. Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20(11):1566–1575. doi:10.1016/S1470-2045(19)30617-5
  77. Ladra MM, Szymonifka JD, Mahajan A, et al. Preliminary results of a phase II trial of proton radiotherapy for pediatric rhabdomyosarcoma. J Clin Oncol. 2014;32(33):3762–3770. doi:10.1200/JCO.2014.56.1548
  78. McDonald MW, Esiashvili N, George BA, et al. Intensity-modulated radiotherapy with use of cone-down boost for pediatric head-and-neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys. 2008;72(3):884–891. doi:10.1016/j.ijrobp.2008.01.058
  79. Saltzman AF, Cost NG. Current treatment of pediatric bladder and prostate rhabdomyosarcoma. Curr Urol Rep. 2018;19(1):11. doi:10.1007/s11934-018-0761-8
  80. Terezakis SA, Wharam MD. Radiotherapy for rhabdomyosarcoma: Indications and outcome. Clin Oncol. 2013;25(1):27–35. doi:10.1016/j.clon.2012.07.009
  81. Weigel BJ, Breitfeld PP, Hawkins D, Crist WM, Baker KS. Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. J Pediatr Hematol Oncol. 2001;23(5):272–276. doi:10.1097/00043426-200106000-00007
  82. Arndt CAS, Stoner JA, Hawkins DS, et al. Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: Children’s Oncology Group Study D9803. J Clin Oncol. 2009;27(31):5182–5188. doi:10.1200/JCO.2009.22.3768
  83. Mercado G, Barr F. Fusions involving PAX and FOX genes in the molecular pathogenesis of alveolar rhabdomyosarcoma: Recent advances. Curr Mol Med. 2007;7(1):47–61. doi:10.2174/156652407779940440
  84. Williamson D, Missiaglia E, Chisholm J, Shipley J. Inconvenience of convenience cohort: Letter. Cancer Epidemiol Biomarkers Prev. 2012;21(8):1388. doi:10.1158/1055-9965.EPI-12-0724
  85. Vo TT, Ryan J, Carrasco R, et al. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell. 2012;151(2):344–355. doi:10.1016/j.cell.2012.08.038
  86. Gryder BE, Yohe ME, Chou HC, et al. PAX3–FOXO1 establishes myogenic super enhancers and confers BET bromodomain vulnerability. Cancer Discov. 2017;7(8):884–899. doi:10.1158/2159-8290.CD-16-1297
  87. Salesse S, Verfaillie CM. BCR/ABL: From molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia. Oncogene. 2002;21(56):8547–8559. doi:10.1038/sj.onc.1206082
  88. Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46(10):1773–1780. doi:10.1016/j.ejca.2010.04.002
  89. Chen C, Dorado Garcia H, Scheer M, Henssen AG. Current and future treatment strategies for rhabdomyosarcoma. Front Oncol. 2019;9:1458. doi:10.3389/fonc.2019.01458
  90. Wan X, Yeung C, Heske C, Mendoza A, Helman LJ. IGF-1R inhibition activates a YES/SFK bypass resistance pathway: Rational basis for co-targeting IGF-1R and Yes/SFK kinase in rhabdomyosarcoma. Neoplasia. 2015;17(4):358–366. doi:10.1016/j.neo.2015.03.001
  91. van Gaal JC, Roeffen MHS, Flucke UE, et al. Simultaneous targeting of insulin-like growth factor-1 receptor and anaplastic lymphoma kinase in embryonal and alveolar rhabdomyosarcoma: A rational choice. Eur J Cancer. 2013;49(16):3462–3470. doi:10.1016/j.ejca.2013.06.022
  92. van den Broeke LT, Pendleton CD, Mackall C, Helman LJ, Berzofsky JA. Identification and epitope enhancement of a PAX-FKHR fusion protein breakpoint epitope in alveolar rhabdomyosarcoma cells created by a tumorigenic chromosomal translocation inducing CTL capable of lysing human tumors. Cancer Res. 2006;66(3):1818–1823. doi:10.1158/0008-5472.CAN-05-2549
  93. Camero S, Ceccarelli S, De Felice F, et al. PARP inhibitors affect growth, survival and radiation susceptibility of human alveolar and embryonal rhabdomyosarcoma cell lines. J Cancer Res Clin Oncol. 2019;145(1):137–152. doi:10.1007/s00432-018-2774-6
  94. Fulda S. Promises and challenges of Smac mimetics as cancer therapeutics. Clin Cancer Res. 2015;21(22):5030–5036. doi:10.1158/1078-0432.CCR-15-0365
  95. Dobson CC, Naing T, Beug ST, et al. Oncolytic virus synergizes with Smac mimetic compounds to induce rhabdomyosarcoma cell death in a syngeneic murine model. Oncotarget. 2017;8(2):3495–3508. doi:10.18632/oncotarget.13849
  96. Heinicke U, Haydn T, Kehr S, Vogler M, Fulda S. BCL-2 selective inhibitor ABT-199 primes rhabdomyosarcoma cells to histone deacetylase inhibitor-induced apoptosis. Oncogene. 2018;37(39):5325–5339. doi:10.1038/s41388-018-0212-5
  97. Damia G, D’Incalci M. Mechanisms of resistance to alkylating agents. Cytotechnology. 1998;27(1/3):165–173. doi:10.1023/A:1008060720608
  98. Malhotra V, Perry MC. Classical chemotherapy: Mechanisms, toxicities and the therapeutc window. Cancer Biol Ther. 2003;2(Suppl 1):1–3. doi:10.4161/cbt.199
  99. Lind MJ. Principles of cytotoxic chemotherapy. Medicine (Baltimore). 2008;36(1):19–23. doi:10.1016/j.mpmed.2007.10.003
  100. Zółtowska K, Sobczak M. Perspectives of use of polymer carriers of epidoxorubicin and cyclophosphamide in cancer therapy [in Polish]. Polim Med. 2014;44(1):51–62. PMID:24918656.
  101. Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The different mechanisms of cancer drug resistance: A brief review. Adv Pharm Bull. 2017;7(3):339–348. doi:10.15171/apb.2017.041
  102. Kaseb H, Kuhn J, Babiker HM. Rhabdomyosarcoma. In: StatPearls. Treasure Island, USA: StatPearls Publishing; 2022:Bookshelf ID: NBK507721. Accessed February 13, 2023.
  103. Luo H, Vong CT, Chen H, et al. Naturally occurring anti-cancer compounds: Shining from Chinese herbal medicine. Chin Med. 2019;14(1):48. doi:10.1186/s13020-019-0270-9
  104. Enam SF, Kilic CY, Huang J, et al. Cytostatic hypothermia and its impact on glioblastoma and survival. Sci Adv. 2022;8(47):eabq4882. doi:10.1126/sciadv.abq4882
  105. Hashem S, Ali TA, Akhtar S, et al. Targeting cancer signaling pathways by natural products: Exploring promising anti-cancer agents. Biomed Pharmacother. 2022;150:113054. doi:10.1016/j.biopha.2022.113054
  106. Naeem M, Iqbal MO, Khan H, et al. A review of twenty years of research on the regulation of signaling pathways by natural products in breast cancer. Molecules. 2022;27(11):3412. doi:10.3390/molecules27113412
  107. Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod. 2016;79(3):629–661. doi:10.1021/acs.jnatprod.5b01055
  108. Cragg GM, Newman DJ. Plants as a source of anti-cancer agents. J Ethnopharmacol. 2005;100(1–2):72–79. doi:10.1016/j.jep.2005.05.011
  109. Bernardini S, Tiezzi A, Laghezza Masci V, Ovidi E. Natural products for human health: An historical overview of the drug discovery approaches. Nat Prod Res. 2018;32(16):1926–1950. doi:10.1080/14786419.2017.1356838
  110. Nobili S, Lippi D, Witort E, et al. Natural compounds for cancer treatment and prevention. Pharmacol Res. 2009;59(6):365–378. doi:10.1016/j.phrs.2009.01.017
  111. Sauter ER. Cancer prevention and treatment using combination therapy with natural compounds. Exp Rev Clin Pharmacol. 2020;13(3):265–285. doi:10.1080/17512433.2020.1738218
  112. Wilson L, Jordan MA. New microtubule/tubulin-targeted anticancer drugs and novel chemotherapeutic strategies. J Chemother. 2004;16(Suppl 4):83–85. doi:10.1179/joc.2004.16.Supplement-1.83
  113. Altinoz MA, Ozpinar A, Alturfan EE, Elmaci I. Vinorelbine’s anti-tumor actions may depend on the mitotic apoptosis, autophagy and inflammation: Hypotheses with implications for chemo-immunotherapy of advanced cancers and pediatric gliomas. J Chemother. 2018;30(4):203–212. doi:10.1080/1120009X.2018.1487149
  114. Magge RS, DeAngelis LM. The double-edged sword: Neurotoxicity of chemotherapy. Blood Rev. 2015;29(2):93–100. doi:10.1016/j.blre.2014.09.012
  115. Kudlowitz D, Muggia F. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel): Extending its indications. Exp Opin Drug Safety. 2014;13(6):681–685. doi:10.1517/14740338.2014.910193
  116. Willson ML, Burke L, Ferguson T, Ghersi D, Nowak AK, Wilcken N. Taxanes for adjuvant treatment of early breast cancer. Cochrane Database Syst Rev. 2019;9(9):CD004421. doi:10.1002/14651858.CD004421.pub3
  117. Li Y, Yu H, Han F, Wang M, Luo Y, Guo X. Biochanin A induces S phase arrest and apoptosis in lung cancer cells. Biomed Res Int. 2018;2018:3545376. doi:10.1155/2018/3545376
  118. Cheng YM, Shen CJ, Chang CC, Chou CY, Tsai CC, Hsu YC. Inducement of apoptosis by cucurbitacin E, a tetracyclic triterpenes, through death receptor 5 in human cervical cancer cell lines. Cell Death Discov. 2017;3(1):17014. doi:10.1038/cddiscovery.2017.14
  119. Delgado JL, Hsieh CM, Chan NL, Hiasa H. Topoisomerases as anticancer targets. Biochem J. 2018;475(2):373–398. doi:10.1042/BCJ20160583
  120. Venditto VJ, Simanek EE. Cancer therapies utilizing the camptothecins: A review of the in vivo literature. Mol Pharm. 2010;7(2):307–349. doi:10.1021/mp900243b
  121. Marinello J, Delcuratolo M, Capranico G. Anthracyclines as topoisomerase II poisons: From early studies to new perspectives. Int J Mol Sci. 2018;19(11):3480. doi:10.3390/ijms19113480
  122. Seca A, Pinto D. Plant secondary metabolites as anticancer agents: Successes in clinical trials and therapeutic application. Int J Mol Sci. 2018;19(1):263. doi:10.3390/ijms19010263
  123. Ashraf MA. Phytochemicals as potential anticancer drugs: Time to ponder nature’s bounty. Biomed Res Int. 2020;2020:8602879. doi:10.1155/2020/8602879
  124. Kim SJ, Kim HS, Seo YR. Understanding of ROS-inducing strategy in anticancer therapy. Oxid Med Cell Longev. 2019;2019:5381692. doi:10.1155/2019/5381692
  125. Batool T, Makky EA, Jalal M, Yusoff MM. A comprehensive review on l-asparaginase and its applications. Appl Biochem Biotechnol. 2016;178(5):900–923. doi:10.1007/s12010-015-1917-3
  126. Khalifa SAM, Elias N, Farag MA, et al. Marine natural products: A source of novel anticancer drugs. Marine Drugs. 2019;17(9):491. doi:10.3390/md17090491
  127. Marshall AD, Grosveld GC. Alveolar rhabdomyosarcoma: The molecular drivers of PAX3/7-FOXO1-induced tumorigenesis. Skelet Muscle. 2012;2(1):25. doi:10.1186/2044-5040-2-25
  128. Shrestha R, Mohankumar K, Martin G, et al. Flavonoids kaempferol and quercetin are nuclear receptor 4A1 (NR4A1, Nur77) ligands and inhibit rhabdomyosarcoma cell and tumor growth. J Exp Clin Cancer Res. 2021;40(1):392. doi:10.1186/s13046-021-02199-9
  129. Ciolino HP, Clarke R, Yeh GC, Plouzek CA. Inhibition of P-glycoprotein activity and reversal of multidrug resistance in vitro by rosemary extract. Eur J Cancer. 1999;35(10):1541–1545. doi:10.1016/S0959-8049(99)00180-X
  130. Peng CH, Su JD, Chyau CC, et al. Supercritical fluid extracts of rosemary leaves exhibit potent anti-inflammation and anti-tumor effects. Biosci Biotechnol Biochem. 2007;71(9):2223–2232. doi:10.1271/bbb.70199
  131. Ibañez E, Kubátová A, Señoráns FJ, Cavero S, Reglero G, Hawthorne SB. Subcritical water extraction of antioxidant compounds from rosemary plants. J Agric Food Chem. 2003;51(2):375–382. doi:10.1021/jf025878j
  132. Kakouri E, Nikola O, Kanakis C, et al. Cytotoxic effect of Rosmarinus officinalis extract on glioblastoma and rhabdomyosarcoma cell lines. Molecules. 2022;27(19):6348. doi:10.3390/molecules27196348
  133. Urla C, Stagno MJ, Fuchs J, Warmann SW, Schmid E. Anticancer bioactivity of zerumbone on pediatric rhabdomyosarcoma cells [published online as ahead of print on August 5, 2022]. J Cancer Res Clin Oncol. 2022. doi:10.1007/s00432-022-04237-1
  134. Sorg C, Schmid E, Bortel N, Fuchs J, Ellerkamp V. Antitumor effects of curcumin in pediatric rhabdomyosarcoma in combination with chemotherapy and phototherapy in vitro. Int J Oncol. 2020;58(2):266–274. doi:10.3892/ijo.2020.5155
  135. Maqsood M, Qureshi R, Ikram M, et al. Preliminary screening of methanolic plant extracts against human rhabdomyosarcoma cell line from salt range, Pakistan. Pak J Bot. 2022;47(1):353–357. Accessed October 11, 2022.
  136. Meng FC, Wu ZF, Yin ZQ, Lin LG, Wang R, Zhang QW. Coptidis rhizoma and its main bioactive components: Recent advances in chemical investigation, quality evaluation and pharmacological activity. Chin Med. 2018;13:13. doi:10.1186/s13020-018-0171-3
  137. Ferrari A, Gasparini P, Casanova M. A home run for rhabdomyosarcoma after 30 years: What now? Tumori. 2020;106(1):5–11. doi:10.1177/0300891619888021
  138. Jabeen S, Hanif M, Mumtaz Khan M, Khan Quadri M. Natural products sources and their active compounds on disease prevention: A review. Int J Chem Biol Sci. 2016;6:76–83. Accessed October 11, 2022.
  139. Mushtaq S, Abbasi BH, Uzair B, Abbasi R. Natural products as reservoirs of novel therapeutic agents. EXCLIJ. 2018;17:420–451. doi:10.17179/EXCLI2018-1174
  140. Dubińska-Magiera M, Niedbalska-Tarnowska J, Migocka-Patrzałek M, Posyniak E, Daczewska M. Characterization of Hspb8 in zebrafish. Cells. 2020;9(6):1562. doi:10.3390/cells9061562
  141. Dubińska-Magiera M, Migocka-Patrzałek M, Lewandowski D, Daczewska M, Jagla K. Zebrafish as a model for the study of lipid-lowering drug-induced myopathies. Int J Mol Sci. 2021;22(11):5654. doi:10.3390/ijms22115654
  142. Migocka-Patrzałek M, Lewicka A, Elias M, Daczewska M. The effect of muscle glycogen phosphorylase (Pygm) knockdown on zebrafish morphology. Int J Biochem Cell Biol. 2020;118:105658. doi:10.1016/j.biocel.2019.105658
  143. Migocka-Patrzałek M, Elias M. Muscle glycogen phosphorylase and its functional partners in health and disease. Cells. 2021;10(4):883. doi:10.3390/cells10040883
  144. Niedbalska-Tarnowska J, Ochenkowska K, Migocka-Patrzałek M, Dubińska-Magiera M. Assessment of the preventive effect of L-carnitine on post-statin muscle damage in a zebrafish model. Cells. 2022;11(8):1297. doi:10.3390/cells11081297
  145. Plantié E, Migocka-Patrzałek M, Daczewska M, Jagla K. Model organisms in the fight against muscular dystrophy: Lessons from drosophila and zebrafish. Molecules. 2015;20(4):6237–6253. doi:10.3390/molecules20046237
  146. Feitsma H, Cuppen E. Zebrafish as a cancer model. Mol Cancer Res. 2008;6(5):685–694. doi:10.1158/1541-7786.MCR-07-2167
  147. Bian C, Chen W, Ruan Z, et al. Genome and transcriptome sequencing of casper and roy zebrafish mutants provides novel genetic clues for iridophore loss. Int J Mol Sci. 2020;21(7):2385. doi:10.3390/ijms21072385
  148. Yan C, Yang Q, Do D, Brunson DC, Langenau DM. Adult immune compromised zebrafish for xenograft cell transplantation studies. EBioMedicine. 2019;47:24–26. doi:10.1016/j.ebiom.2019.08.016
  149. Zhang B, Xuan C, Ji Y, Zhang W, Wang D. Zebrafish xenotransplantation as a tool for in vivo cancer study. Fam Cancer. 2015;14(3):487–493. doi:10.1007/s10689-015-9802-3