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Perillyl alcohol for pediatric TP53- and RAS-mutated SHH-medulloblastoma: an in vitro and in vivo translational pre-clinical study

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Abstract

Purpose

Inhalation of perillyl alcohol (POH) recently emerged as an investigational promising antiglioma strategy. However, little attention has been paid to its therapeutic potential for other brain tumors, especially in the pediatric setting.

Methods

The effects of POH were explored in medulloblastoma cell models belonging to the SHH variant with activation of RAS (ONS-76) or with TP53 mutations (DAOY and UW402), by means of proliferation and invasion assays. Interactions with methotrexate, thiotepa, or ionizing radiation were also assessed. Mice bearing subcutaneous tumors were treated with intraperitoneal injections. Alternatively, animals with intracranial tumors were exposed to intranasal POH alone or combined with radiation. Tumor growth was measured by bioluminescence. Analyses of cytotoxicity to the nasal cavity were also performed, and the presence of POH in the brain, lungs, and plasma was surveyed through chromatography/mass spectrometry.

Results

POH decreased cell proliferation and colony formation, with conspicuous death, though the invasive capacity was only affected in the NRAS-mutated cell line. Median-drug effect analysis displayed synergistic combinations with methotrexate. Otherwise, POH showed to be a reasonable radiosensitizer. In vivo, intraperitoneal injection significantly decreased tumor volume. However, its inhalation did not affect orthotopic tumors, neither alone or followed by cranial irradiation. Nasal cavity epithelium showed unimportant alterations, though, no traces of POH or its metabolites were detected in tissue samples.

Conclusion

POH presents robust in vitro antimedulloblastoma effects and sensitizes cell lines to other conventional therapeutics, reducing tumor volume when administered intraperitoneally. Nevertheless, further improvement of delivery devices and/or drug formulations are needed to better characterize its effectiveness through inhalation.

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References

  1. Markouli M, Strepkos D, Papavassiliou AG, Piperi C (2020) Targeting of endoplasmic reticulum (ER) stress in gliomas. Pharmacol Res 157:104823. https://doi.org/10.1016/j.phrs.2020.104823

    Article  CAS  PubMed  Google Scholar 

  2. Azimi H, Khakshur AA, Abdollahi M, Rahimi R (2015) Potential new pharmacological agents derived from medicinal plants for the treatment of pancreatic cancer. Pancreas 44:11–15. https://doi.org/10.1097/MPA.0000000000000175

    Article  CAS  PubMed  Google Scholar 

  3. Chung BH, Lee H, Lee JS, Young CYF (2006) Perillyl alcohol inhibits the expression and function of the androgen receptor in human prostate cancer cells. Cancer Lett 236:222–228. https://doi.org/10.1016/j.canlet.2005.05.023

    Article  CAS  PubMed  Google Scholar 

  4. Koyama M, Sowa Y, Hitomi T, Iizumi Y, Watanabe M, Taniguchi T, Ichikawa M, Sakai T (2013) Perillyl alcohol causes G1 arrest through p15INK4b and p21WAF1/Cip1 induction. Oncol Rep 29:779–784. https://doi.org/10.3892/or.2012.2167

    Article  CAS  PubMed  Google Scholar 

  5. Oturanel CE, Kiran I, Özsen Ö et al (2017) Cytotoxic, antiproliferative and apoptotic effects of perillyl alcohol and its biotransformation metabolite on A549 and HepG2 cancer cell lines. Anti Cancer Agents Med Chem 17. https://doi.org/10.2174/1871520617666170103093923

  6. Reddy BS, Wang CX, Samaha H, Lubet R, Steele VE, Kelloff GJ, Rao CV (1997) Chemoprevention of colon carcinogenesis by dietary perillyl alcohol. Cancer Res 57:420–425

    CAS  PubMed  Google Scholar 

  7. Stark MJ, Burke YD, McKinzie JH et al (1995) Chemotherapy of pancreatic cancer with the monoterpene perillyl alcohol. Cancer Lett 96:15–21. https://doi.org/10.1016/0304-3835(95)03912-G

    Article  CAS  PubMed  Google Scholar 

  8. Stayrook K (1997) Induction of the apoptosis-promoting protein Bak by perillyl alcohol in pancreatic ductal adenocarcinoma relative to untransformed ductal epithelial cells. Carcinogenesis 18:1655–1658. https://doi.org/10.1093/carcin/18.8.1655

    Article  CAS  PubMed  Google Scholar 

  9. Wiseman DA, Werner SR, Crowell PL (2007) Cell cycle arrest by the isoprenoids perillyl alcohol, geraniol, and farnesol is mediated by p21 Cip1 and p27 Kip1 in human pancreatic adenocarcinoma cells. J Pharmacol Exp Ther 320:1163–1170. https://doi.org/10.1124/jpet.106.111666

    Article  CAS  PubMed  Google Scholar 

  10. Yeruva L, Hall C, Elegbede JA, Carper SW (2010) Perillyl alcohol and methyl jasmonate sensitize cancer cells to cisplatin. Anti-Cancer Drugs 21:1–9. https://doi.org/10.1097/CAD.0b013e32832a68ad

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gomes AC, Mello AL, Ribeiro MG, Garcia DG, da Fonseca CO, Salazar MD’A, Schönthal AH, Quirico-Santos T (2017) Perillyl alcohol, a pleiotropic natural compound suitable for brain tumor therapy, targets free radicals. Arch Immunol Ther Exp (Warsz) 65:285–297. https://doi.org/10.1007/s00005-017-0459-5

    Article  CAS  Google Scholar 

  12. Berndt N, Hamilton AD, Sebti SM (2011) Targeting protein prenylation for cancer therapy. Nat Rev Cancer 11:775–791. https://doi.org/10.1038/nrc3151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Campbell PM, Groehler AL, Lee KM, Ouellette MM, Khazak V, der CJ (2007) K-Ras promotes growth transformation and invasion of immortalized human pancreatic cells by Raf and phosphatidylinositol 3-kinase signaling. Cancer Res 67:2098–2106. https://doi.org/10.1158/0008-5472.CAN-06-3752

    Article  CAS  PubMed  Google Scholar 

  14. Crowell PL, Chang RR, Ren ZB, Elson CE, Gould MN (1991) Selective inhibition of isoprenylation of 21-26-kDa proteins by the anticarcinogen d-limonene and its metabolites. J Biol Chem 266:17679–17685

    Article  CAS  Google Scholar 

  15. Gelb MH, Tamanoi F, Yokoyama K, Ghomashchi F, Esson K, Gould MN (1995) The inhibition of protein prenyltransferases by oxygenated metabolites of limonene and perillyl alcohol. Cancer Lett 91:169–175. https://doi.org/10.1016/0304-3835(95)03747-K

    Article  CAS  PubMed  Google Scholar 

  16. Ren Z, Elson CE, Gould MN (1997) Inhibition of type I and type II geranylgeranyl-protein transferases by the monoterpene perillyl alcohol in NIH3T3 cells. Biochem Pharmacol 54:113–120. https://doi.org/10.1016/S0006-2952(97)00151-2

    Article  CAS  PubMed  Google Scholar 

  17. Stayrook KR, McKinzie JH, Barbhaiya LH, Crowell PL (1998) Effects of the antitumor agent perillyl alcohol on H-Ras vs. K-Ras farnesylation and signal transduction in pancreatic cells. Anticancer Res 18:823–828

    CAS  PubMed  Google Scholar 

  18. Bailey HH, Attia S, Love RR, Fass T, Chappell R, Tutsch K, Harris L, Jumonville A, Hansen R, Shapiro GR, Stewart JA (2008) Phase II trial of daily oral perillyl alcohol (NSC 641066) in treatment-refractory metastatic breast cancer. Cancer Chemother Pharmacol 62:149–157. https://doi.org/10.1007/s00280-007-0585-6

    Article  CAS  PubMed  Google Scholar 

  19. Ripple GH, Gould MN, Arzoomanian RZ, Alberti D, Feierabend C, Simon K, Binger K, Tutsch KD, Pomplun M, Wahamaki A, Marnocha R, Wilding G, Bailey HH (2000) Phase I clinical and pharmacokinetic study of perillyl alcohol administered four times a day. Clin Cancer Res 6:390–396

    CAS  PubMed  Google Scholar 

  20. Ripple GH, Gould MN, Stewart JA, Tutsch KD, Arzoomanian RZ, Alberti D, Feierabend C, Pomplun M, Wilding G, Bailey HH (1998) Phase I clinical trial of perillyl alcohol administered daily. Clin Cancer Res 4:1159–1164

    CAS  PubMed  Google Scholar 

  21. Chen T, da Fonseca C, Schönthal A (2018) Intranasal perillyl alcohol for glioma therapy: molecular mechanisms and clinical development. Int J Mol Sci 19:3905. https://doi.org/10.3390/ijms19123905

    Article  CAS  PubMed Central  Google Scholar 

  22. da Fonseca CO, Landeiro JA, Clark SS, Quirico-Santos T, da Costa Carvalho MG, Gattass CR (2006) Recent advances in the molecular genetics of malignant gliomas disclose targets for antitumor agent perillyl alcohol. Surg Neurol 65:S2–S8. https://doi.org/10.1016/j.surneu.2005.06.030

    Article  Google Scholar 

  23. Chou AJ, Gupta R, Bell MD, Riewe KO'D, Meyers PA, Gorlick R (2013) Inhaled lipid cisplatin (ILC) in the treatment of patients with relapsed/progressive osteosarcoma metastatic to the lung. Pediatr Blood Cancer 60:580–586. https://doi.org/10.1002/pbc.24438

    Article  CAS  PubMed  Google Scholar 

  24. Huang S, Yang J-Y (2015) Targeting the hedgehog pathway in pediatric medulloblastoma. Cancers (Basel) 7:2110–2123. https://doi.org/10.3390/cancers7040880

    Article  CAS  Google Scholar 

  25. Milde T, Lodrini M, Savelyeva L, Korshunov A, Kool M, Brueckner LM, Antunes ASLM, Oehme I, Pekrun A, Pfister SM, Kulozik AE, Witt O, Deubzer HE (2012) HD-MB03 is a novel group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment. J Neuro-Oncol 110:335–348. https://doi.org/10.1007/s11060-012-0978-1

    Article  CAS  Google Scholar 

  26. Milde T, Oehme I, Korshunov A, Kopp-Schneider A, Remke M, Northcott P, Deubzer HE, Lodrini M, Taylor MD, von Deimling A, Pfister S, Witt O (2010) HDAC5 and HDAC9 in medulloblastoma: novel markers for risk stratification and role in tumor cell growth. Clin Cancer Res 16:3240–3252. https://doi.org/10.1158/1078-0432.CCR-10-0395

    Article  CAS  PubMed  Google Scholar 

  27. Gajjar A, Stewart CF, Ellison DW, Kaste S, Kun LE, Packer RJ, Goldman S, Chintagumpala M, Wallace D, Takebe N, Boyett JM, Gilbertson RJ, Curran T (2013) Phase I study of vismodegib in children with recurrent or refractory medulloblastoma: a pediatric brain tumor consortium study. Clin Cancer Res 19:6305–6312. https://doi.org/10.1158/1078-0432.CCR-13-1425

    Article  CAS  PubMed  Google Scholar 

  28. Robinson GW, Orr BA, Wu G, Gururangan S, Lin T, Qaddoumi I, Packer RJ, Goldman S, Prados MD, Desjardins A, Chintagumpala M, Takebe N, Kaste SC, Rusch M, Allen SJ, Onar-Thomas A, Stewart CF, Fouladi M, Boyett JM, Gilbertson RJ, Curran T, Ellison DW, Gajjar A (2015) Vismodegib exerts targeted efficacy against recurrent sonic hedgehog–subgroup medulloblastoma: results from phase II pediatric brain tumor consortium studies PBTC-025B and PBTC-032. J Clin Oncol 33:2646–2654. https://doi.org/10.1200/JCO.2014.60.1591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kieran MW, Chisholm J, Casanova M, Brandes AA, Aerts I, Bouffet E, Bailey S, Leary S, MacDonald TJ, Mechinaud F, Cohen KJ, Riccardi R, Mason W, Hargrave D, Kalambakas S, Deshpande P, Tai F, Hurh E, Geoerger B (2017) Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma. Neuro-Oncology 19:1542–1552. https://doi.org/10.1093/neuonc/nox109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Menyhárt O, Győrffy B (2019) Principles of tumorigenesis and emerging molecular drivers of <scp>SHH</scp>-activated medulloblastomas. Ann Clin Transl Neurol 6:990–1005. https://doi.org/10.1002/acn3.762

    Article  PubMed  PubMed Central  Google Scholar 

  31. Zhao X, Ponomaryov T, Ornell KJ, Zhou P, Dabral SK, Pak E, Li W, Atwood SX, Whitson RJ, Chang ALS, Li J, Oro AE, Chan JA, Kelleher JF, Segal RA (2015) RAS/MAPK activation drives resistance to Smo inhibition, metastasis, and tumor evolution in Shh pathway-dependent tumors. Cancer Res 75:3623–3635. https://doi.org/10.1158/0008-5472.CAN-14-2999-T

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ivanov DP, Coyle B, Walker DA, Grabowska AM (2016) In vitro models of medulloblastoma: choosing the right tool for the job. J Biotechnol 236:10–25. https://doi.org/10.1016/j.jbiotec.2016.07.028

    Article  CAS  PubMed  Google Scholar 

  33. Cruzeiro GAV, Salomão KB, de Biagi Jr CAO, Baumgartner M, Sturm D, Lira RCP, de Almeida Magalhães T, Baroni Milan M, da Silva Silveira V, Saggioro FP, de Oliveira RS, dos Santos Klinger PH, Seidinger AL, Yunes JA, de Paula Queiroz RG, Oba-Shinjo SM, Scrideli CA, Nagahashi SMK, Tone LG, Valera ET (2019) A simplified approach using Taqman low-density array for medulloblastoma subgrouping. Acta Neuropathol Commun 7:33. https://doi.org/10.1186/s40478-019-0681-y

    Article  PubMed  PubMed Central  Google Scholar 

  34. Bobola MS (2005) Apurinic/apyrimidinic endonuclease activity is associated with response to radiation and chemotherapy in medulloblastoma and primitive neuroectodermal tumors. Clin Cancer Res 11:7405–7414. https://doi.org/10.1158/1078-0432.CCR-05-1068

    Article  CAS  PubMed  Google Scholar 

  35. Kunkele A, De Preter K, Heukamp L et al (2012) Pharmacological activation of the p53 pathway by nutlin-3 exerts anti-tumoral effects in medulloblastomas. Neuro-Oncology 14:859–869. https://doi.org/10.1093/neuonc/nos115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zomerman WW, Plasschaert SLA, Conroy S, Scherpen FJ, Meeuwsen-de Boer TGJ, Lourens HJ, Guerrero Llobet S, Smit MJ, Slagter-Menkema L, Seitz A, Gidding CEM, Hulleman E, Wesseling P, Meijer L, van Kempen LC, van den Berg A, Warmerdam DO, Kruyt FAE, Foijer F, van Vugt MATM, den Dunnen WFA, Hoving EW, Guryev V, de Bont ESJM, Bruggeman SWM (2018) Identification of two protein-signaling states delineating transcriptionally heterogeneous human medulloblastoma. Cell Rep 22:3206–3216. https://doi.org/10.1016/j.celrep.2018.02.089

    Article  CAS  PubMed  Google Scholar 

  37. dos Santos Klinger PH, Delsin LEA, Cruzeiro GAV, Andrade AF, Lira RCP, de Andrade PV, das Chagas PF, de Paula Queiroz RG, Trevisan FA, de Oliveira RS, Scrideli CA, Tone LG, Valera ET (2020) Arsenic trioxide exerts cytotoxic and radiosensitizing effects in pediatric medulloblastoma cell lines of SHH subgroup. Sci Rep 10:6836. https://doi.org/10.1038/s41598-020-63808-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lee Y, Shacter E (1999) Oxidative stress inhibits apoptosis in human lymphoma cells. J Biol Chem 274:19792–19798. https://doi.org/10.1074/jbc.274.28.19792

    Article  CAS  PubMed  Google Scholar 

  39. Liang C-C, Park AY, Guan J-L (2007) In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2:329–333. https://doi.org/10.1038/nprot.2007.30

    Article  CAS  PubMed  Google Scholar 

  40. Roberto GM, Paiva HH, Botelho de Souza LE, Pezuk JA, Vieira GM, de Oliveira HF, Umezawa K, Tone LG, Brassesco MS (2019) DTCM-glutarimide delays growth and radiosensitizes glioblastoma. Anti Cancer Agents Med Chem 18:1323–1329. https://doi.org/10.2174/1871520618666180423105740

    Article  CAS  Google Scholar 

  41. Yuri T, Danbara N, Tsujita-Kyutoku M, Kiyozuka Y, Senzaki H, Shikata N, Kanzaki H, Tsubura A (2004) Perillyl alcohol inhibits human breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 84:251–260. https://doi.org/10.1023/B:BREA.0000019966.97011.4d

    Article  CAS  PubMed  Google Scholar 

  42. Gholamin S, Feroze AH, Mitra SS, Kahn SA, Cheshier SH (2013) Establishment of stereotactic orthotopic brain tumor xenografts in mice: technical report. Cureus. https://doi.org/10.7759/cureus.150

  43. D’Alincourt Salazar M, da Silva RF, Da Fonseca CO et al (2014) Intranasal administration of perillyl alcohol activates peripheral and bronchus-associated immune system in vivo. Arch

  44. Geyer JR, Sposto R, Jennings M, Boyett JM, Axtell RA, Breiger D, Broxson E, Donahue B, Finlay JL, Goldwein JW, Heier LA, Johnson D, Mazewski C, Miller DC, Packer R, Puccetti D, Radcliffe J, Tao ML, Shiminski-Maher T, Children's Cancer Group (2005) Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the children’s cancer group. J Clin Oncol 23:7621–7631. https://doi.org/10.1200/JCO.2005.09.095

    Article  PubMed  Google Scholar 

  45. Dhall G, Grodman H, Ji L, Sands S, Gardner S, Dunkel IJ, McCowage GB, Diez B, Allen JC, Gopalan A, Cornelius AS, Termuhlen A, Abromowitch M, Sposto R, Finlay JL (2008) Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the “Head Start” I and II protocols. Pediatr Blood Cancer 50:1169–1175. https://doi.org/10.1002/pbc.21525

    Article  PubMed  Google Scholar 

  46. da Fonseca CO, Simão M, Lins IR, Caetano RO, Futuro D, Quirico-Santos T (2011) Efficacy of monoterpene perillyl alcohol upon survival rate of patients with recurrent glioblastoma. J Cancer Res Clin Oncol 137:287–293. https://doi.org/10.1007/s00432-010-0873-0

    Article  CAS  PubMed  Google Scholar 

  47. da Fonseca CO, Schwartsmann G, Fischer J, Nagel J, Futuro D, Quirico-Santos T, Gattass CR (2008) Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas. Surg Neurol 70:259–266. https://doi.org/10.1016/j.surneu.2007.07.040

    Article  PubMed  Google Scholar 

  48. Chaudhary SC, Alam MS, Siddiqui MS, Athar M (2009) Perillyl alcohol attenuates Ras-ERK signaling to inhibit murine skin inflammation and tumorigenesis. Chem Biol Interact 179:145–153. https://doi.org/10.1016/j.cbi.2008.12.016

    Article  CAS  PubMed  Google Scholar 

  49. Lluria-Prevatt M, Morreale J, Gregus J et al (2002) Effects of perillyl alcohol on melanoma in the TPras mouse model. Cancer Epidemiol Biomark Prev 11:573–579

    CAS  Google Scholar 

  50. Sundin T, Peffley DM, Gauthier D, Hentosh P (2012) The isoprenoid perillyl alcohol inhibits telomerase activity in prostate cancer cells. Biochimie 94:2639–2648. https://doi.org/10.1016/j.biochi.2012.07.028

    Article  CAS  PubMed  Google Scholar 

  51. Castro-Gamero AM, Borges KS, Lira RC, Andrade AF, Fedatto PF, Cruzeiro GAV, Silva RB, Fontes AM, Valera ET, Bobola M, Scrideli CA, Tone LG (2013) Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype. Cytotechnology 65:871–885. https://doi.org/10.1007/s10616-012-9529-z

    Article  PubMed  PubMed Central  Google Scholar 

  52. He XM, Ostrowski LE, von Wronski MA, Friedman HS, Wikstrand CJ, Bigner SH, Rasheed A, Batra SK, Mitra S, Brent TP (1992) Expression of O6-methylguanine-DNA methyltransferase in six human medulloblastoma cell lines. Cancer Res 52:1144–1148

    CAS  PubMed  Google Scholar 

  53. Siddik ZH (2005) Mechanisms of action of cancer chemotherapeutic agents: DNA-interactive alkylating agents and antitumour platinum-based drugs. In: The Cancer Handbook. John Wiley & Sons, Ltd, Chichester

  54. Rajesh D, Stenzel RA, Howard SP (2003) Perillyl alcohol as a radio-/chemosensitizer in malignant glioma. J Biol Chem 278:35968–35978. https://doi.org/10.1074/jbc.M303280200

    Article  CAS  PubMed  Google Scholar 

  55. Gómez-Contreras PC, Hernández-Flores G, Ortiz-Lazareno PC, del Toro-Arreola S, Delgado-Rizo V, Lerma-Díaz JM, Barba-Barajas M, Domínguez-Rodríguez JR, Bravo Cuellar A (2006) In vitro induction of apoptosis in U937 cells by perillyl alcohol with sensitization by pentoxifylline: increased BCL-2 and BAX protein expression. Chemotherapy 52:308–315. https://doi.org/10.1159/000096003

    Article  CAS  PubMed  Google Scholar 

  56. Cho H-Y, Wang W, Jhaveri N, Torres S, Tseng J, Leong MN, Lee DJ, Goldkorn A, Xu T, Petasis NA, Louie SG, Schönthal AH, Hofman FM, Chen TC (2012) Perillyl alcohol for the treatment of temozolomide-resistant gliomas. Mol Cancer Ther 11:2462–2472. https://doi.org/10.1158/1535-7163.MCT-12-0321

    Article  CAS  PubMed  Google Scholar 

  57. Rajesh D, Howard SP (2003) Perillyl alcohol mediated radiosensitization via augmentation of the Fas pathway in prostate cancer cells. Prostate 57:14–23. https://doi.org/10.1002/pros.10269

    Article  CAS  PubMed  Google Scholar 

  58. Djupesland PG (2013) Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv Transl Res 3:42–62. https://doi.org/10.1007/s13346-012-0108-9

    Article  CAS  PubMed  Google Scholar 

  59. Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM (2001) Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a children’s cancer group study. J Clin Oncol 19:3470–3476. https://doi.org/10.1200/JCO.2001.19.15.3470

    Article  CAS  PubMed  Google Scholar 

  60. Mulhern RK, Palmer SL, Reddick WE, Glass JO, Kun LE, Taylor J, Langston J, Gajjar A (2001) Risks of young age for selected neurocognitive deficits in medulloblastoma are associated with white matter loss. J Clin Oncol 19:472–479. https://doi.org/10.1200/JCO.2001.19.2.472

    Article  CAS  PubMed  Google Scholar 

  61. Jamison S, Lin Y, Lin W (2015) Pancreatic endoplasmic reticulum kinase activation promotes medulloblastoma cell migration and invasion through induction of vascular endothelial growth factor A. PLoS One 10:e0120252. https://doi.org/10.1371/journal.pone.0120252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. DA Fonseca CO, Teixeira RM, Silva JCT et al (2013) Long-term outcome in patients with recurrent malignant glioma treated with perillyl alcohol inhalation. Anticancer Res 33:5625–5631

    Google Scholar 

  63. Zhang Z, Chen H, Chan KK, Budd T, Ganapathi R (1999) Gas chromatographic-mass spectrometric analysis of perillyl alcohol and metabolites in plasma. J Chromatogr B Biomed Sci Appl 728:85–95

    Article  CAS  Google Scholar 

  64. Murren JR, Pizzorno G, DiStasio SA et al (2002) Phase I study of perillyl alcohol in patients with refractory malignancies. Cancer Biol Ther 1:130–135. https://doi.org/10.4161/cbt.57

    Article  CAS  PubMed  Google Scholar 

  65. Lima DC, Rodrigues SV, Boaventura GT, Cho HY, Chen TC, Schönthal AH, da Fonseca CO (2020) Simultaneous measurement of perillyl alcohol and its metabolite perillic acid in plasma and lung after inhalational administration in Wistar rats. Drug Test Anal 12:268–279. https://doi.org/10.1002/dta.2722

    Article  CAS  PubMed  Google Scholar 

  66. Anselmo AC, Gokarn Y, Mitragotri S (2019) Non-invasive delivery strategies for biologics. Nat Rev Drug Discov 18:19–40. https://doi.org/10.1038/nrd.2018.183

    Article  CAS  PubMed  Google Scholar 

  67. Dhuria SV, Hanson LR, Frey WH (2010) Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci 99:1654–1673. https://doi.org/10.1002/jps.21924

    Article  CAS  PubMed  Google Scholar 

  68. Chen T, Da Fonseca C, Schönthal A (2016) Perillyl alcohol and its drug-conjugated derivatives as potential novel methods of treating brain metastases. Int J Mol Sci 17:1463. https://doi.org/10.3390/ijms17091463

    Article  CAS  PubMed Central  Google Scholar 

  69. Chen T, Chan N, Labib S et al (2018) Induction of pro-apoptotic endoplasmic reticulum stress in multiple myeloma cells by NEO214, perillyl alcohol conjugated to rolipram. Int J Mol Sci

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Acknowledgments

The authors would like to thank Ieda Regina dos Santos and Cleide Lucia Araujo Silva for their assistance with the in vivo model, and Elderes de Paula, who performed the irradiation of animals. We also thank Adriana de Andrade Batista Murashima and Marina Zilio Fantucci for technical support.

Funding

This study was supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) Proc. N° 2013/23881-2 and 2016/08125-5.

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Authors and Affiliations

  1. Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil

    Marcela de Oliveira Silva, Graziella Ribeiro de Sousa, Sarah Capelupe Simões, Edwin Tamashiro, Fabiano Saggioro & Ricardo Santos de Oliveira

  2. Physics Department from the Faculty of Philosophy, Sciences and Letters at Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil

    Patrícia Nicolucci

  3. Laboratory of Cell Biology and Oncogenetics, Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Av. Bandeirantes, 3900, Bairro Monte Alegre, Ribeirão Preto, São Paulo, CEP 14040-900, Brazil

    María Sol Brassesco

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Correspondence to María Sol Brassesco.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed were in accordance with the ethical standards of the institutional Committee on Ethics in the Use of Animals (CEUA) from the University of São Paulo Ribeirão Preto Campus (Protocol 14.1.541.53.8).

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Supplementary figure 1

Chromatograms with retention time of standard POH samples and spectrometer with fragmentation and mass of this compound. A) POH at a concentration of 500μg/ml; B) POH at a concentration of 50μg/ml. (PNG 75 kb)

High resolution image (TIF 5175 kb)

Supplementary figure 2

Representative chromatograms of brain, lung and plasma samples from control and POH-treated mice. No POH could be detected in any of the samples. A) Control group without receiving any treatment B) Group treated with 84μg POH collected after 15 min; C) Samples from the group treated with a dose of 84 μg POH, collected after 2 hours. (PNG 56 kb)

High resolution image (TIF 3813 kb)

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Silva, M., de Sousa, G.R., Simões, S.C. et al. Perillyl alcohol for pediatric TP53- and RAS-mutated SHH-medulloblastoma: an in vitro and in vivo translational pre-clinical study. Childs Nerv Syst 37, 2163–2175 (2021). https://doi.org/10.1007/s00381-021-05115-w

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  • DOI: https://doi.org/10.1007/s00381-021-05115-w

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