Skip to content
2000
image of Participation of MDM2 in Pro-Apoptotic and Androgen Receptor-Degrading Potency of Selected Steroid and Terpenoid Derivatives

Abstract

This review aims to highlight anti-proliferative, pro-apoptotic, and androgen receptor-degrading activity of selected steroid and terpenoid derivatives in cancer cells, primarily in prostate cancer cells. Steroid and terpenoid derivatives (steroid hybrids, comprising androstane or pregnane skeleton associated with nitrogen containing heterocycle, some natural sterols, bile acids, and related semi-synthetic derivatives; oleanane and ursane type pentacyclic triterpenoids; lanostane and dammarane type tetracyclic triterpenoids), were reported earlier to cause the death of cancer cells apoptosis; some compounds exhibited significant anticancer potency and may be considered as promising anticancer agents. The presented data indicate that direct interaction of steroid and terpenoid derivatives with the key oncogenic protein MDM2 makes a significant contribution to anti-proliferative, pro-apoptotic, and androgen receptor-degrading activity of these compounds. It triggers apoptosis, which leads to cell death. Structural optimization of steroid and terpenoid derivatives can significantly increase their affinity to MDM2 and improve their anti-proliferative, pro-apoptotic, and androgen receptor-degrading activity.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673373971250625075309
2025-08-04
2025-11-04

  • From This Site

    /content/journals/cmc/10.2174/0109298673373971250625075309
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Njar V.C.O. Brodie A.M.H. Discovery and development of Galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer. J. Med. Chem. 2015 58 5 2077 2087 10.1021/jm501239f 25591066
    [Google Scholar]
  2. Njar V.C.O. Androgen receptor antagonism and impact on inhibitors of androgen synthesis in prostate cancer therapy. Transl. Cancer Res. 2017 6 S7 S1128 S1131 10.21037/tcr.2017.08.29 30613487
    [Google Scholar]
  3. Latysheva A.S. Zolottsev V.A. Pokrovsky V.S. Khan I.I. Misharin A.Y. Novel nitrogen containing steroid derivatives for prostate cancer treatment. Curr. Med. Chem. 2021 28 40 8416 8432 10.2174/0929867328666210208113919 33557730
    [Google Scholar]
  4. Huo H. Li G. Shi B. Li J. Recent advances on synthesis and biological activities of C-17 aza-heterocycle derived steroids. Bioorg. Med. Chem. 2022 69 116882 10.1016/j.bmc.2022.116882 35749841
    [Google Scholar]
  5. Hou Y. Shang C. Meng T. Lou W. Anticancer potential of cardiac glycosides and steroid-azole hybrids. Steroids 2021 171 108852 10.1016/j.steroids.2021.108852 33887267
    [Google Scholar]
  6. Patlolla J.M.R. Rao C.V. Triterpenoids for cancer prevention and treatment: Current status and future prospects. Curr. Pharm. Biotechnol. 2012 13 1 147 155 10.2174/138920112798868719 21466427
    [Google Scholar]
  7. Gupta N. A review on recent developments in the anticancer potential of oleanolic acid and its analogs (2017-2020). Mini Rev. Med. Chem. 2022 22 4 600 616 10.2174/1389557521666210810153627 35135459
    [Google Scholar]
  8. Hussain H. Ali I. Wang D. Hakkim F.L. Westermann B. Ahmed I. Ashour A.M. Khan A. Hussain A. Green I.R. Shah S.T.A. Glycyrrhetinic acid: A promising scaffold for the discovery of anticancer agents. Expert Opin. Drug Discov. 2021 16 12 1497 1516 10.1080/17460441.2021.1956901 34294017
    [Google Scholar]
  9. Lombrea A. Scurtu A.D. Avram S. Pavel I.Z. Turks M. Lugiņina J. Peipiņš U. Dehelean C.A. Soica C. Danciu C. Anticancer potential of betulonic acid derivatives. Int. J. Mol. Sci. 2021 22 7 3676 10.3390/ijms22073676 33916089
    [Google Scholar]
  10. Banerjee J. Samanta S. Ahmed R. Dash S.K. Bioactive pentacyclic triterpenes trigger multiple signalling pathways for selective apoptosis leading to anticancer efficacy: Recent updates and future perspectives. Curr. Protein Pept. Sci. 2023 24 10 820 842 10.2174/1389203724666230418123409 37073661
    [Google Scholar]
  11. Nistor G. Trandafirescu C. Prodea A. Milan A. Cristea A. Ghiulai R. Racoviceanu R. Mioc A. Mioc M. Ivan V. Șoica C. Semisynthetic derivatives of pentacyclic triterpenes bearing heterocyclic moieties with therapeutic potential. Molecules 2022 27 19 6552 10.3390/molecules27196552 36235089
    [Google Scholar]
  12. Khwaza V. Mlala S. Oyedeji O.O. Aderibigbe B.A. Pentacyclic triterpenoids with nitrogen-containing heterocyclic moiety, privileged hybrids in anticancer drug discovery. Molecules 2021 26 9 2401 10.3390/molecules26092401 33918996
    [Google Scholar]
  13. Ferreira I.C.F.R. Vaz J.A. Vasconcelos M.H. Martins A. Compounds from wild mushrooms with antitumor potential. Anticancer. Agents Med. Chem. 2010 10 5 424 436 10.2174/1871520611009050424 20545620
    [Google Scholar]
  14. Liang C. Tian D. Liu Y. Li H. Zhu J. Li M. Xin M. Xia J. Review of the molecular mechanisms of Ganoderma lucidum triterpenoids: Ganoderic acids A, C2, D, F, DM, X and Y. Eur. J. Med. Chem. 2019 174 130 141 10.1016/j.ejmech.2019.04.039 31035236
    [Google Scholar]
  15. Ameri A. Ganoderic Acid in the treatment of prostate cancer. Jundishapur J. Nat. Pharm. Prod. 2012 7 3 85 86 10.17795/jjnpp‑7171 24624160
    [Google Scholar]
  16. Wang W. Zhao Y. Rayburn E.R. Hill D.L. Wang H. Zhang R. In vitro anti-cancer activity and structure-activity relationships of natural products isolated from fruits of Panax ginseng. Cancer Chemother. Pharmacol. 2007 59 5 589 601 10.1007/s00280‑006‑0300‑z 16924497
    [Google Scholar]
  17. Nag S.A. Qin J-J. Wang W. Wang M-H. Wang H. Zhang R. Ginsenosides as anticancer agents: In vitro and in vivo activities, structure-activity relationships, and molecular mechanisms of action. Front. Pharmacol. 2012 3 25 10.3389/fphar.2012.00025 22403544
    [Google Scholar]
  18. Wong A.S.T. Che C.M. Leung K.W. Recent advances in ginseng as cancer therapeutics: A functional and mechanistic overview. Nat. Prod. Rep. 2015 32 2 256 272 10.1039/C4NP00080C 25347695
    [Google Scholar]
  19. Majeed F. Malik F.Z. Ahmed Z. Afreen A. Afzal M.N. Khalid N. Ginseng phytochemicals as therapeutics in oncology: Recent perspectives. Biomed. Pharmacother. 2018 100 52 63 10.1016/j.biopha.2018.01.155 29421582
    [Google Scholar]
  20. Tan M.M. Chen M.H. Han F. Wang J.W. Tu Y.X. Role of bioactive constituents of Panax notoginseng in the modulation of tumorigenesis: A potential review for the treatment of cancer. Front. Pharmacol. 2021 12 738914 10.3389/fphar.2021.738914 34776959
    [Google Scholar]
  21. Yao W. Guan Y. Ginsenosides in cancer: A focus on the regulation of cell metabolism. Biomed. Pharmacother. 2022 156 113756 10.1016/j.biopha.2022.113756 36228372
    [Google Scholar]
  22. Yang Y. Nan Y. Du Y. Liu W. Ning N. Chen G. Gu Q. Yuan L. Ginsenosides in cancer: Proliferation, metastasis, and drug resistance. Biomed. Pharmacother. 2024 177 117049 10.1016/j.biopha.2024.117049 38945081
    [Google Scholar]
  23. Vargas D.A. Takahashi S. Ronai Z. Mdm2: A regulator of cell growth and death. Adv. Cancer Res. 2003 89 1 34 10.1016/S0065‑230X(03)01001‑7 14587869
    [Google Scholar]
  24. Dobbelstein M. Levine A.J. Mdm2: Open questions. Cancer Sci. 2020 111 7 2203 2211 10.1111/cas.14433 32335977
    [Google Scholar]
  25. Koo N. Sharma A.K. Narayan S. Therapeutics targeting p53-MDM2 interaction to induce cancer cell death. Int. J. Mol. Sci. 2022 23 9 5005 10.3390/ijms23095005 35563397
    [Google Scholar]
  26. Rayburn E. Ezell S. Zhang R. Recent advances in validating MDM2 as a cancer target. Anticancer. Agents Med. Chem. 2009 9 8 882 903 10.2174/187152009789124628 19538162
    [Google Scholar]
  27. Qin J.J. Li X. Hunt C. Wang W. Wang H. Zhang R. Natural products targeting the p53-MDM2 pathway and mutant p53: Recent advances and implications in cancer medicine. Genes Dis. 2018 5 3 204 219 10.1016/j.gendis.2018.07.002 30320185
    [Google Scholar]
  28. Wang W. Albadari N. Du Y. Fowler J.F. Sang H.T. Xian W. McKeon F. Li W. Zhou J. Zhang R. MDM2 inhibitors for cancer therapy: The past, present, and future. Pharmacol. Rev. 2024 76 3 414 453 10.1124/pharmrev.123.001026 38697854
    [Google Scholar]
  29. Grossebrummel H. Peter T. Mandelkow R. Weiss M. Muzzio D. Zimmermann U. Walther R. Jensen F. Knabbe C. Zygmunt M. Burchardt M. Stope M.B. Cytochrome P450 17A1 inhibitor abiraterone attenuates cellular growth of prostate cancer cells independently from androgen receptor signaling by modulation of oncogenic and apoptotic pathways. Int. J. Oncol. 2016 48 2 793 800 10.3892/ijo.2015.3274 26648519
    [Google Scholar]
  30. Soifer H.S. Souleimanian N. Wu S. Voskresenskiy A.M. Collak F.K. Cinar B. Stein C.A. Prostate cancer cells activity by potent CYP17 inhibitors in direct regulation of androgen receptor. J. Biol. Chem. 2012 287 6 3777 3787 10.1074/jbc.M111.261933 22174412
    [Google Scholar]
  31. Bruno R.D. Gover T.D. Burger A.M. Brodie A.M. Njar V.C.O. 17α-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response. Mol. Cancer Ther. 2008 7 9 2828 2836 10.1158/1535‑7163.MCT‑08‑0336 18790763
    [Google Scholar]
  32. Vasaitis T. Belosay A. Schayowitz A. Khandelwal A. Chopra P. Gediya L.K. Guo Z. Fang H.B. Njar V.C.O. Brodie A.M.H. Androgen receptor inactivation contributes to antitumor efficacy of 17α-hydroxylase/17,20-lyase inhibitor 3β-hydroxy-17-(1 H -benzimidazole-1-yl)androsta-5,16-diene in prostate cancer. Mol. Cancer Ther. 2008 7 8 2348 2357 10.1158/1535‑7163.MCT‑08‑0230 18723482
    [Google Scholar]
  33. Purushottamachar P. Godbole A.M. Gediya L.K. Martin M.S. Vasaitis T.S. Kwegyir-Afful A.K. Ramalingam S. Ates-Alagoz Z. Njar V.C.O. Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer. J. Med. Chem. 2013 56 12 4880 4898 10.1021/jm400048v 23713567
    [Google Scholar]
  34. Purushottamachar P. Kwegyir-Afful A.K. Martin M.S. Ramamurthy V.P. Ramalingam S. Njar V.C.O. Identification of novel steroidal androgen receptor degrading agents inspired by galeterone 3β-imidazole carbamate. ACS Med. Chem. Lett. 2016 7 7 708 713 10.1021/acsmedchemlett.6b00137 27437082
    [Google Scholar]
  35. Wang A. Luo X. Wang Y. Meng X. Lu Z. Yang Y. Design, synthesis, and biological evaluation of androgen receptor degrading and antagonizing bifunctional steroidal analogs for the treatment of advanced prostate cancer. J. Med. Chem. 2022 65 18 12460 12481 10.1021/acs.jmedchem.2c01164 36070471
    [Google Scholar]
  36. Kwegyir-Afful A.K. Ramalingam S. Purushottamachar P. Ramamurthy V.P. Njar V.C.O. Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo. Oncotarget 2015 6 29 27440 27460 10.18632/oncotarget.4578 26196320
    [Google Scholar]
  37. McClurg U.L. Azizyan M. Dransfield D.T. Namdev N. Chit N.C.T.H. Nakjang S. Robson C.N. The novel anti-androgen candidate galeterone targets deubiquitinating enzymes, USP12 and USP46, to control prostate cancer growth and survival. Oncotarget 2018 9 38 24992 25007 10.18632/oncotarget.25167 29861848
    [Google Scholar]
  38. Thomas E. Thankan R.S. Purushottamachar P. Njar V.C.O. Abstract LBA027: Mechanistic insights on the effects of the lead next generation galeterone analog, VNPP433-3β in castration resistant prostate cancer. Mol. Cancer Ther. 2021 20 12_Supplement LBA027 LBA7 10.1158/1535‑7163.TARG‑21‑LBA027
    [Google Scholar]
  39. Thomas E. Thankan R.S. Purushottamachar P. Weber D.J. Njar V.C.O. Targeted degradation of androgen receptor by VNPP433-3β in castration-resistant prostate cancer cells implicates interaction with E3 ligase MDM2 resulting in ubiquitin-proteasomal degradation. Cancers 2023 15 4 1198 10.3390/cancers15041198 36831540
    [Google Scholar]
  40. Thomas E. Thankan R.S. Purushottamachar P. Huang W. Kane M.A. Zhang Y. Ambulos N.P. Weber D.J. Njar V.C.O. Novel AR/AR-V7 and Mnk1/2 degrader, VNPP433-3β: Molecular mechanisms of action and efficacy in AR-overexpressing castration resistant prostate cancer in vitro and in vivo models. Cells 2022 11 17 2699 10.3390/cells11172699 36078112
    [Google Scholar]
  41. McCarty D.J. Huang W. Kane M.A. Purushottamachar P. Gediya L.K. Njar V.C.O. Novel galeterone analogs act independently of AR and AR-V7 for the activation of the unfolded protein response and induction of apoptosis in the CWR22Rv1 prostate cancer cell model. Oncotarget 2017 8 51 88501 88516 10.18632/oncotarget.19762 29179452
    [Google Scholar]
  42. Kwegyir-Afful A.K. Ramalingam S. Ramamurthy V.P. Purushottamachar P. Murigi F.N. Vasaitis T.S. Huang W. Kane M.A. Zhang Y. Ambulos N. Tiwari S. Srivastava P. Nnane I.P. Hussain A. Qiu Y. Weber D.J. Njar V.C.O. Galeterone and the next generation galeterone analogs, VNPP414 and VNPP433-3β exert potent therapeutic effects in castration-/drug-resistant prostate cancer preclinical models in vitro and in vivo. Cancers 2019 11 11 1637 10.3390/cancers11111637 31653008
    [Google Scholar]
  43. Kwegyir-Afful A.K. Bruno R.D. Purushottamachar P. Murigi F.N. Njar V.C.O. Galeterone and VNPT 55 disrupt Mnk‐ eIF 4E to inhibit prostate cancer cell migration and invasion. FEBS J. 2016 283 21 3898 3918 10.1111/febs.13895 27618366
    [Google Scholar]
  44. Xu Y. Liao S. Wang L. Wang Y. Wei W. Su K. Tu Y. Zhu S. Galeterone sensitizes breast cancer to chemotherapy via targeting MNK/eIF4E and β-catenin. Cancer Chemother. Pharmacol. 2021 87 1 85 93 10.1007/s00280‑020‑04195‑w 33159561
    [Google Scholar]
  45. Kwegyir-Afful A.K. Murigi F.N. Purushottamachar P. Ramamurthy V.P. Martin M.S. Njar V.C.O. Galeterone and its analogs inhibit Mnk-eIF4E axis, synergize with gemcitabine, impede pancreatic cancer cell migration, invasion and proliferation and inhibit tumor growth in mice. Oncotarget 2017 8 32 52381 52402 10.18632/oncotarget.14154 28881737
    [Google Scholar]
  46. Baston E. Leroux F. Inhibitors of steroidal cytochrome p450 enzymes as targets for drug development. Recent Patents Anticancer Drug Discov. 2007 2 1 31 58 10.2174/157489207779561453 18221052
    [Google Scholar]
  47. Moreira V. Salvador J. Vasaitis T. Njar V. CYP17 inhibitors for prostate cancer treatment--an update. Curr. Med. Chem. 2008 15 9 868 899 10.2174/092986708783955428 18473796
    [Google Scholar]
  48. Owen C.P. 17α-hydroxylase/17,20-lyase (p450(17α)) inhibitors in the treatment of prostate cancer: A review. Anticancer. Agents Med. Chem. 2009 9 6 613 626 10.2174/187152009788680046 19601745
    [Google Scholar]
  49. Vasaitis T.S. Bruno R.D. Njar V.C.O. CYP17 inhibitors for prostate cancer therapy. J. Steroid Biochem. Mol. Biol. 2011 125 1-2 23 31 10.1016/j.jsbmb.2010.11.005 21092758
    [Google Scholar]
  50. Salvador J.A.R. Pinto R.M.A. Silvestre S.M. Steroidal 5α-reductase and 17α-hydroxylase/17,20-lyase (CYP17) inhibitors useful in the treatment of prostatic diseases. J. Steroid Biochem. Mol. Biol. 2013 137 199 222 10.1016/j.jsbmb.2013.04.006 23688836
    [Google Scholar]
  51. Salvador J.A.R. Moreira V.M. Silvestre S.M. Steroidal CYP17 inhibitors for prostate cancer treatment: From concept to clinic. Advances in Prostate Cancer Hamilton G. InTechOpen London, UK 2013 10.5772/52290
    [Google Scholar]
  52. Frank É. Schneider G. Synthesis of sex hormone-derived modified steroids possessing antiproliferative activity. J. Steroid Biochem. Mol. Biol. 2013 137 301 315 10.1016/j.jsbmb.2013.02.018 23499871
    [Google Scholar]
  53. Cabeza M. Sánchez-Márquez A. Garrido M. Silva A. Bratoeff E. Recent advances in drug design and drug discovery for androgen-dependent diseases. Curr. Med. Chem. 2016 23 8 792 815 10.2174/0929867323666160210125642 26861003
    [Google Scholar]
  54. Kuzminac I.Z. Nikolić A.R. Savić M.P. Ajduković J.J. Abiraterone and galeterone, powerful tools against prostate cancer: Present and perspective. Pharmaceutics 2024 16 11 1401 10.3390/pharmaceutics16111401 39598525
    [Google Scholar]
  55. Zolottsev V.A. Latysheva A.S. Khan I.I. Pokrovsky V.S. Misharin A.Y. Design and synthesis of new agents for prostate cancer treatment inspired by steroidal CYP17 A1 inhibitors. ChemistrySelect 2022 7 45 202203393 10.1002/slct.202203393
    [Google Scholar]
  56. Khan I.I. Karshieva S.S. Sokolova D.V. Spirina T.S. Zolottsev V.A. Latysheva A.S. Anisimova N.Y. Komarova M.V. Yakunina M.N. Nitetskaya T.A. Misharin A.Y. Pokrovsky V.S. Antiproliferative, proapoptotic, and tumor‐suppressing effects of the novel anticancer agent alsevirone in prostate cancer cells and xenografts. Arch. Pharm. 2022 355 1 2100316 10.1002/ardp.202100316 34668210
    [Google Scholar]
  57. Latysheva A.S. Zolottsev V.A. Veselovsky A.V. Scherbakov K.A. Morozevich G.E. Zhdanov D.D. Novikov R.A. Misharin A.Y. Oxazolinyl derivatives of androst-16-ene as inhibitors of CYP17A1 activity and prostate carcinoma cells proliferation: Effects of substituents in oxazolinyl moiety. J. Steroid Biochem. Mol. Biol. 2023 230 106280 10.1016/j.jsbmb.2023.106280 36870373
    [Google Scholar]
  58. Jakimov D.S. Kojić V.V. Aleksić L.D. Bogdanović G.M. Ajduković J.J. Djurendić E.A. Penov Gaši K.M. Sakač M.N. Jovanović-Šanta S.S. Androstane derivatives induce apoptotic death in MDA-MB-231 breast cancer cells. Bioorg. Med. Chem. 2015 23 22 7189 7198 10.1016/j.bmc.2015.10.015 26494582
    [Google Scholar]
  59. Shi Y.K. Wang B. Shi X.L. Zhao Y.D. Yu B. Liu H.M. Synthesis and biological evaluation of new steroidal pyridines as potential anti-prostate cancer agents. Eur. J. Med. Chem. 2018 145 11 22 10.1016/j.ejmech.2017.12.094 29310026
    [Google Scholar]
  60. Komendantova A.S. Scherbakov A.M. Komkov A.V. Chertkova V.V. Gudovanniy A.O. Chernoburova E.I. Sorokin D.V. Dzichenka Y.U. Shirinian V.Z. Volkova Y.A. Zavarzin I.V. Novel steroidal 1,3,4-thiadiazines: Synthesis and biological evaluation in androgen receptor-positive prostate cancer 22Rv1 cells. Bioorg. Chem. 2019 91 103142 10.1016/j.bioorg.2019.103142 31400555
    [Google Scholar]
  61. Yang Y.T. Du S. Wang S. Jia X. Wang X. Zhang X. Synthesis of new steroidal quinolines with antitumor properties. Steroids 2019 151 108465 10.1016/j.steroids.2019.108465 31351940
    [Google Scholar]
  62. Yu B. Yu D.Q. Liu H.M. Spirooxindoles: Promising scaffolds for anticancer agents. Eur. J. Med. Chem. 2015 97 673 698 10.1016/j.ejmech.2014.06.056 24994707
    [Google Scholar]
  63. Shi X.J. Yu B. Wang J.W. Qi P.P. Tang K. Huang X. Liu H.M. Structurally novel steroidal spirooxindole by241 potently inhibits tumor growth mainly through ROS-mediated mechanisms. Sci. Rep. 2016 6 1 31607 10.1038/srep31607 27527552
    [Google Scholar]
  64. Yu B. Sun X.N. Shi X.J. Qi P.P. Zheng Y.C. Yu D.Q. Liu H.M. Efficient synthesis of novel antiproliferative steroidal spirooxindoles via the [3+2] cycloaddition reactions of azomethine ylides. Steroids 2015 102 92 100 10.1016/j.steroids.2015.08.003 26256638
    [Google Scholar]
  65. Yu B. Shi X.J. Qi P.P. Yu D.Q. Liu H.M. Design, synthesis and biological evaluation of novel steroidal spiro-oxindoles as potent antiproliferative agents. J. Steroid Biochem. Mol. Biol. 2014 141 121 134 10.1016/j.jsbmb.2014.01.015 24508598
    [Google Scholar]
  66. Amaral J.D. Castro R.E. Solá S. Steer C.J. Rodrigues C.M.P. Ursodeoxycholic acid modulates the ubiquitin-proteasome degradation pathway of p53. Biochem. Biophys. Res. Commun. 2010 400 4 649 654 10.1016/j.bbrc.2010.08.121 20807506
    [Google Scholar]
  67. Vogel S.M. Bauer M.R. Joerger A.C. Wilcken R. Brandt T. Veprintsev D.B. Rutherford T.J. Fersht A.R. Boeckler F.M. Lithocholic acid is an endogenous inhibitor of MDM4 and MDM2. Proc. Natl. Acad. Sci. USA 2012 109 42 16906 16910 10.1073/pnas.1215060109 23035244
    [Google Scholar]
  68. Ren Y. Wu S. Chen S. Burdette J.E. Cheng X. Kinghorn A.D. Interaction of (+)-strebloside and its derivatives with Na+/K+-ATPase and other targets. Molecules 2021 26 18 5675 10.3390/molecules26185675 34577146
    [Google Scholar]
  69. Xiao Y. Xu B. Li X. Ding T. Zhao W. Nie X. Mu J. Xiao Z. Wang Q. Ren Q. Zhang E. Potential targets of diosgenin for the treatment of oral squamous cell carcinoma and their bioinformatics and transcriptional profiling analyses. Steroids 2024 205 109393 10.1016/j.steroids.2024.109393 38458369
    [Google Scholar]
  70. Wang W. Li C. Chen Z. Zhang J. Ma L. Tian Y. Ma Y. Guo L. Wang X. Ye J. Wang X. Novel diosgenin-amino acid-benzoic acid mustard trihybrids exert antitumor effects via cell cycle arrest and apoptosis. J. Steroid Biochem. Mol. Biol. 2022 216 106038 10.1016/j.jsbmb.2021.106038 34861390
    [Google Scholar]
  71. Wang Z. Zhan Y. Xu J. Wang Y. Sun M. Chen J. Liang T. Wu L. Xu K. β-Sitosterol reverses multidrug resistance via BCRP suppression by inhibiting the p53−MDM2 interaction in colorectal cancer. J. Agric. Food Chem. 2020 68 12 3850 3858 10.1021/acs.jafc.0c00107 32167760
    [Google Scholar]
  72. Dolfi S.C. Jäger A.V. Medina D.J. Haffty B.G. Yang J.M. Hirshfield K.M. Fulvestrant treatment alters MDM2 protein turnover and sensitivity of human breast carcinoma cells to chemotherapeutic drugs. Cancer Lett. 2014 350 1-2 52 60 10.1016/j.canlet.2014.04.009 24747123
    [Google Scholar]
  73. Kim G.J. Jo H.J. Lee K.J. Choi J.W. An J.H. Oleanolic acid induces p53-dependent apoptosis via the ERK/JNK/AKT pathway in cancer cell lines in prostatic cancer xenografts in mice. Oncotarget 2018 9 41 26370 26386 10.18632/oncotarget.25316 29899865
    [Google Scholar]
  74. Li X. Song Y. Zhang P. Zhu H. Chen L. Xiao Y. Xing Y. Oleanolic acid inhibits cell survival and proliferation of prostate cancer cells in vitro and in vivo through the PI3K/Akt pathway. Tumour Biol. 2016 37 6 7599 7613 10.1007/s13277‑015‑4655‑9 26687646
    [Google Scholar]
  75. Kassi E. Papoutsi Z. Pratsinis H. Aligiannis N. Manoussakis M. Moutsatsou P. Ursolic acid, a naturally occurring triterpenoid, demonstrates anticancer activity on human prostate cancer cells. J. Cancer Res. Clin. Oncol. 2007 133 7 493 500 10.1007/s00432‑007‑0193‑1 17516089
    [Google Scholar]
  76. Meng Y. Lin Z.M. Ge N. Zhang D.L. Huang J. Kong F. Ursolic acid induces apoptosis of prostate cancer cells via the PI3K/Akt/mTOR pathway. Am. J. Chin. Med. 2015 43 7 1471 1486 10.1142/S0192415X15500834 26503559
    [Google Scholar]
  77. Shankar E. Zhang A. Franco D. Gupta S. Betulinic acid-mediated apoptosis in human prostate cancer cells involves p53 and nuclear factor-kappa B (NF-κB) pathways. Molecules 2017 22 2 264 10.3390/molecules22020264 28208611
    [Google Scholar]
  78. Chintharlapalli S. Papineni S. Ramaiah S.K. Safe S. Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res. 2007 67 6 2816 2823 10.1158/0008‑5472.CAN‑06‑3735 17363604
    [Google Scholar]
  79. Reiner T. Parrondo R. de las Pozas A. Palenzuela D. Perez-Stable C. Betulinic acid selectively increases protein degradation and enhances prostate cancer-specific apoptosis: Possible role for inhibition of deubiquitinase activity. PLoS One 2013 8 2 56234 10.1371/journal.pone.0056234 23424652
    [Google Scholar]
  80. de las Pozas A. Reiner T. De Cesare V. Trost M. Perez-Stable C. Inhibiting multiple deubiquitinases to reduce androgen receptor expression in prostate cancer cells. Sci. Rep. 2018 8 1 13146 10.1038/s41598‑018‑31567‑3 30177856
    [Google Scholar]
  81. Gnanasekar M. Thirugnanam S. Dakshinamoorthy G. Samykutty A. Zheng G. Chen A. Bosland M.C. Kajdacsy-Balla A. Gnanasekar M. 18α-glycyrrhetinic acid targets prostate cancer cells by down-regulating inflammation-related genes. Int. J. Oncol. 2011 39 3 635 640 10.3892/ijo.2011.1061 21637916
    [Google Scholar]
  82. Frolova T.S. Lipeeva A.V. Baev D.S. Tsepilov Y.A. Sinitsyna O.I. Apoptosis as the basic mechanism of cytotoxic action of ursolic and pomolic acids in glioma cells. Mol. Biol. 2017 51 5 705 711 10.1134/S0026893317050090 29116067
    [Google Scholar]
  83. Muhseen Z.T. Li G. Promising terpenes as natural antagonists of cancer: An in-silico approach. Molecules 2019 25 1 155 10.3390/molecules25010155 31906032
    [Google Scholar]
  84. Csuk R. Betulinic acid and its derivatives: A patent review (2008-2013). Expert Opin. Ther. Pat. 2014 24 8 913 923 10.1517/13543776.2014.927441 24909232
    [Google Scholar]
  85. Baer-Dubowska W. Narożna M. Krajka-Kuźniak V. Anti-cancer potential of synthetic oleanolic acid derivatives and their conjugates with NSAIDs. Molecules 2021 26 16 4957 10.3390/molecules26164957 34443544
    [Google Scholar]
  86. Nistor M. Rugina D. Diaconeasa Z. Socaciu C. Socaciu M.A. Pentacyclic triterpenoid phytochemicals with anticancer activity: Updated studies on mechanisms and targeted delivery. Int. J. Mol. Sci. 2023 24 16 12923 10.3390/ijms241612923 37629103
    [Google Scholar]
  87. Abdelmageed N. Morad S.A.F. Elghoneimy A.A. Syrovets T. Simmet T. El-zorba H. El-Banna H.A. Cabot M. Abdel-Aziz M.I. Oleanolic acid methyl ester, a novel cytotoxic mitocan, induces cell cycle arrest and ROS-Mediated cell death in castration-resistant prostate cancer PC-3 cells. Biomed. Pharmacother. 2017 96 417 425 10.1016/j.biopha.2017.10.027 29031200
    [Google Scholar]
  88. Hao J. Liu J. Wen X. Sun H. Synthesis and cytotoxicity evaluation of oleanolic acid derivatives. Bioorg. Med. Chem. Lett. 2013 23 7 2074 2077 10.1016/j.bmcl.2013.01.129 23434227
    [Google Scholar]
  89. Xu J. Wang X. Zhang H. Yue J. Sun Y. Zhang X. Zhao Y. Synthesis of triterpenoid derivatives and their anti-tumor and anti-hepatic fibrosis activities. Nat. Prod. Res. 2020 34 6 766 772 10.1080/14786419.2018.1499642 30445851
    [Google Scholar]
  90. Honda T. Rounds B.V. Gribble G.W. Suh N. Wang Y. Sporn M.B. Design and synthesis of 2-cyano-3,12-dioxoolean-1,9-dien28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages. Bioorg. Med. Chem. Lett. 1998 8 2711 2714 10.1016/S0960‑894X(98)00479‑X 9873608
    [Google Scholar]
  91. Shanmugam M.K. Dai X. Kumar A.P. Tan B.K.H. Sethi G. Bishayee A. Oleanolic acid and its synthetic derivatives for the prevention and therapy of cancer: Preclinical and clinical evidence. Cancer Lett. 2014 346 2 206 216 10.1016/j.canlet.2014.01.016 24486850
    [Google Scholar]
  92. Borella R. Forti L. Gibellini L. De Gaetano A. De Biasi S. Nasi M. Cossarizza A. Pinti M. Synthesis and anticancer activity of CDDO and CDDO-Me, two derivatives of natural triterpenoids. Molecules 2019 24 22 4097 10.3390/molecules24224097 31766211
    [Google Scholar]
  93. Papineni S. Chintharlapalli S. Safe S. Methyl 2-cyano-3,11-dioxo-18 β-olean-1,12-dien-30-oate is a peroxisome proliferator-activated receptor-γ agonist that induces receptor-independent apoptosis in LNCaP prostate cancer cells. Mol. Pharmacol. 2008 73 2 553 565 10.1124/mol.107.041285 17989348
    [Google Scholar]
  94. Hyer M.L. Shi R. Krajewska M. Meyer C. Lebedeva I.V. Fisher P.B. Reed J.C. Apoptotic activity and mechanism of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic-acid and related synthetic triterpenoids in prostate cancer. Cancer Res. 2008 68 8 2927 2933 10.1158/0008‑5472.CAN‑07‑5759 18413762
    [Google Scholar]
  95. Markov A.V. Odarenko K.V. Ilyina A.A. Zenkova M.A. Uncovering the anti-angiogenic effect of semisynthetic triterpenoid CDDO-Im on HUVECs by an integrated network pharmacology approach. Comput. Biol. Med. 2022 141 105034 10.1016/j.compbiomed.2021.105034 34802714
    [Google Scholar]
  96. Deeb D. Gao X. Jiang H. Dulchavsky S.A. Gautam S.C. Oleanane Triterpenoid CDDO‐Me inhibits growth and induces apoptosis in prostate cancer cells by independently targeting pro‐survival Akt and mTOR. Prostate 2009 69 8 851 860 10.1002/pros.20937 19189297
    [Google Scholar]
  97. Deeb D. Gao X. Jiang H. Janic B. Arbab A.S. Rojanasakul Y. Dulchavsky S.A. Gautam S.C. Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism. Biochem. Pharmacol. 2010 79 3 350 360 10.1016/j.bcp.2009.09.006 19782051
    [Google Scholar]
  98. Liu Y. Gao X. Deeb D. Gautam S.C. Oleanane triterpenoid CDDO-Me inhibits Akt activity without affecting PDK1 kinase or PP2A phosphatase activity in cancer cells. Biochem. Biophys. Res. Commun. 2012 417 1 570 575 10.1016/j.bbrc.2011.12.007 22177954
    [Google Scholar]
  99. Cui H.W. He Y. Wang J. Gao W. Liu T. Qin M. Wang X. Gao C. Wang Y. Liu M.Y. Yi Z. Qiu W.W. Synthesis of heterocycle-modified betulinic acid derivatives as antitumor agents. Eur. J. Med. Chem. 2015 95 240 248 10.1016/j.ejmech.2015.03.048 25817774
    [Google Scholar]
  100. Saxena B. Zhu L. Hao M. Kisilis E. Katdare M. Oktem O. Bomshteyn A. Rathnam P. Boc-lysinated-betulonic acid: A potent, anti-prostate cancer agent. Bioorg. Med. Chem. 2006 14 18 6349 6358 10.1016/j.bmc.2006.05.048 16777417
    [Google Scholar]
  101. Li K. Ma T. Cai J. Huang M. Guo H. Zhou D. Luan S. Yang J. Liu D. Jing Y. Zhao L. Conjugates of 18β-glycyrrhetinic acid derivatives with 3-(1H-benzo[d]imidazol-2-yl)propanoic acid as Pin1 inhibitors displaying anti-prostate cancer ability. Bioorg. Med. Chem. 2017 25 20 5441 5451 10.1016/j.bmc.2017.08.002 28838831
    [Google Scholar]
  102. Popov S.A. Semenova M.D. Baev D.S. Frolova T.S. Shestopalov M.A. Wang C. Qi Z. Shults E.E. Turks M. Synthesis and cytotoxicity of hybrids of 1,3,4- or 1,2,5-oxadiazoles tethered from ursane and lupane core with 1,2,3-triazole. Steroids 2020 162 108698 10.1016/j.steroids.2020.108698 32687846
    [Google Scholar]
  103. Moradali M.F. Mostafavi H. Ghods S. Hedjaroude G.A. Immunomodulating and anticancer agents in the realm of macromycetes fungi (macrofungi). Int. Immunopharmacol. 2007 7 6 701 724 10.1016/j.intimp.2007.01.008 17466905
    [Google Scholar]
  104. Liu J. Shiono J. Shimizu K. Kukita A. Kukita T. Kondo R. Ganoderic acid DM: Anti-androgenic osteoclastogenesis inhibitor. Bioorg. Med. Chem. Lett. 2009 19 8 2154 2157 10.1016/j.bmcl.2009.02.119 19289282
    [Google Scholar]
  105. Jiang J. Grieb B. Thyagarajan A. Sliva D. Ganoderic acids suppress growth and invasive behavior of breast cancer cells by modulating AP-1 and NF-κB signaling. Int. J. Mol. Med. 2008 21 5 577 584 10.3892/ijmm.21.5.577 18425349
    [Google Scholar]
  106. Li C.H. Chen P.Y. Chang U.M. Kan L.S. Fang W.H. Tsai K.S. Lin S.B. Ganoderic acid X, a lanostanoid triterpene, inhibits topoisomerases and induces apoptosis of cancer cells. Life Sci. 2005 77 3 252 265 10.1016/j.lfs.2004.09.045 15878354
    [Google Scholar]
  107. Tang W. Liu J.W. Zhao W.M. Wei D.Z. Zhong J.J. Ganoderic acid T from Ganoderma lucidum mycelia induces mitochondria mediated apoptosis in lung cancer cells. Life Sci. 2006 80 3 205 211 10.1016/j.lfs.2006.09.001 17007887
    [Google Scholar]
  108. Wang X. Sun D. Tai J. Wang L. Ganoderic acid A inhibits proliferation and invasion, and promotes apoptosis in human hepatocellular carcinoma cells. Mol. Med. Rep. 2017 16 4 3894 3900 10.3892/mmr.2017.7048 28731159
    [Google Scholar]
  109. Cheng Y. Xie P. Ganoderic acid A holds promising cytotoxicity on human glioblastoma mediated by incurring apoptosis and autophagy and inactivating PI3K/AKT signaling pathway. J. Biochem. Mol. Toxicol. 2019 33 11 22392 10.1002/jbt.22392 31503386
    [Google Scholar]
  110. Johnson B.M. Radwan F.F.Y. Hossain A. Doonan B.P. Hathaway-Schrader J.D. God J.M. Voelkel-Johnson C.V. Banik N.L. Reddy S.V. Haque A. Endoplasmic reticulum stress, autophagic and apoptotic cell death, and immune activation by a natural triterpenoid in human prostate cancer cells. J. Cell. Biochem. 2019 120 4 6264 6276 10.1002/jcb.27913 30378157
    [Google Scholar]
  111. Jia Y. Li Y. Shang H. Luo Y. Tian Y. Ganoderic acid A and its amide derivatives as potential anti-cancer agents by regulating the p53-MDM2 pathway: Synthesis and biological evaluation. Molecules 2023 28 5 2374 10.3390/molecules28052374 36903622
    [Google Scholar]
  112. Froufe H.J.C. Abreu R.M.V. Ferreira I.C.F.R. Virtual screening of low molecular weight mushrooms compounds as potential Mdm2 inhibitors. J. Enzyme Inhib. Med. Chem. 2013 28 3 569 575 10.3109/14756366.2012.658787 22380771
    [Google Scholar]
  113. Khoury K. Domling A. P53-MDM2 inhibitors. Curr. Pharm. Des. 2012 18 4668 4678 10.2174/138161212802651580 22650254
    [Google Scholar]
  114. Anifowose A. Agbowuro A.A. Yang X. Wang B. Anticancer strategies by upregulating p53 through inhibition of its ubiquitination by MDM2. Med. Chem. Res. 2020 29 7 1105 1121 10.1007/s00044‑020‑02574‑9
    [Google Scholar]
  115. Beloglazkina A. Zyk N. Majouga A. Beloglazkina E. Recent small-molecule inhibitors of the p53-MDM2 protein-protein interaction. Molecules 2020 25 5 1211 10.3390/molecules25051211 32156064
    [Google Scholar]
  116. Ru W. Wang D. Xu Y. He X. Sun Y.E. Qian L. Zhou X. Qin Y. Chemical constituents and bioactivities of Panax ginseng (C. A. Mey.). Drug Discov. Ther. 2015 9 1 23 32 10.5582/ddt.2015.01004 25788049
    [Google Scholar]
  117. Cao J. Zhang X. Qu F. Guo Z. Zhao Y. Dammarane triterpenoids for pharmaceutical use: A patent review (2005-2014). Expert Opin. Ther. Pat. 2015 25 7 805 817 10.1517/13543776.2015.1038239 25892194
    [Google Scholar]
  118. Park J. Bui P.T.C. Song H. Kim S.K. Rhee D.K. Kim E.Y. Rhyu M.R. Lee M.S. Lee Y.J. Ginseng on nuclear hormone receptors. Am. J. Chin. Med. 2017 45 6 1147 1156 10.1142/S0192415X17500628 28830207
    [Google Scholar]
  119. Guo Y. Kuruganti R. Gao Y. Recent Advances in ginsenosides as potential therapeutics against breast cancer. Curr. Top. Med. Chem. 2019 19 25 2334 2347 10.2174/1568026619666191018100848 31648643
    [Google Scholar]
  120. Xiao H. Xue Q. Zhang Q. Li C. Liu X. Liu J. Li H. Yang J. How ginsenosides trigger apoptosis in human lung adenocarcinoma cells. Am. J. Chin. Med. 2019 47 8 1737 1754 10.1142/S0192415X19500885 31795742
    [Google Scholar]
  121. Tian M. Li L.N. Zheng R.R. Yang L. Wang Z.T. Advances on hormone-like activity of Panax ginseng and ginsenosides. Chin. J. Nat. Med. 2020 18 7 526 535 10.1016/S1875‑5364(20)30063‑7 32616193
    [Google Scholar]
  122. Wu S. Ding M. Wang X. Li W. Zhao Y. 25-Methoxyl-dammarane-3β, 12β, 20-triol, a ginseng saponin derivative and an anticancer agent: in vitro and in vivo activities, molecular mechanism of action, pharmacokinetics and structural modification. Med. Chem. 2017 7 3 832 836 10.4172/2161‑0444.1000437
    [Google Scholar]
  123. Wang W. Rayburn E.R. Zhao Y. Wang H. Zhang R. Novel ginsenosides 25-OH-PPD and 25-OCH 3 -PPD as experimental therapy for pancreatic cancer: Anticancer activity and mechanisms of action. Cancer Lett. 2009 278 2 241 248 10.1016/j.canlet.2009.01.005 19203832
    [Google Scholar]
  124. Zhao Y. Wang W. Han L. Rayburn E. Hil D. Wang H. Zhang R. Isolation, structural determination, and evaluation of the biological activity of 20(S)-25-methoxyl-dammarane-3β, 12β, 20-triol [20(S)-25-OCH3-PPD], a novel natural product from Panax notoginseng. Med. Chem. 2007 3 1 51 60 10.2174/157340607779317508 17266624
    [Google Scholar]
  125. Wang W. Wang H. Rayburn E.R. Zhao Y. Hill D.L. Zhang R. 20(S)-25-methoxyl-dammarane-3β, 12β, 20-triol, a novel natural product for prostate cancer therapy: Activity in vitro and in vivo and mechanisms of action. Br. J. Cancer 2008 98 4 792 802 10.1038/sj.bjc.6604227 18253123
    [Google Scholar]
  126. Cao B. Liu X. Li J. Liu S. Qi Y. Xiong Z. Zhang A. Wiese T. Fu X. Gu J. Rennie P.S. Sartor O. Lee B.R. Ip C. Zhao L. Zhang H. Dong Y. 20(S)-protopanaxadiol-aglycone downregulation of the full-length and splice variants of androgen receptor. Int. J. Cancer 2013 132 6 1277 1287 10.1002/ijc.27754 22907191
    [Google Scholar]
  127. Kim D. Park M. Haleem I. Lee Y. Koo J. Na Y.C. Song G. Lee J. Natural product ginsenoside 20(S)-25-methoxyl-dammarane-3β, 12β, 20-triol in cancer treatment: A review of the pharmacological mechanisms and pharmacokinetics. Front. Pharmacol. 2020 11 521 10.3389/fphar.2020.00521 32425780
    [Google Scholar]
  128. Wang W. Qin J.J. Li X. Tao G. Wang Q. Wu X. Zhou J. Zi X. Zhang R. Prevention of prostate cancer by natural product MDM2 inhibitor GS25: in vitro and in vivo activities and molecular mechanisms. Carcinogenesis 2018 39 8 1026 1036 10.1093/carcin/bgy063 29762656
    [Google Scholar]
  129. Liu Y.F. Yuan H.N. Bi X.L. Piao H.R. Cao J.Q. Li W. Wang P. Zhao Y.Q. 25-Methoxylprotopanaxadiol derivatives and their anti-proliferative activities. Steroids 2013 78 14 1305 1311 10.1016/j.steroids.2013.09.010 24120654
    [Google Scholar]
  130. Wang X.D. Sun Y.Y. Zhao C. Qu F.Z. Zhao Y.Q. 12-Chloracetyl-PPD, a novel dammarane derivative, shows anti-cancer activity via delay the progression of cell cycle G2/M phase and reactive oxygen species-mediate cell apoptosis. Eur. J. Pharmacol. 2017 798 49 56 10.1016/j.ejphar.2016.12.027 28017829
    [Google Scholar]
  131. Wang P. Bi X.L. Xu J. Yuan H.N. Piao H.R. Zhao Y.Q. Synthesis and anti-tumor evaluation of novel 25-hydroxyprotopanaxadiol analogs incorporating natural amino acids. Steroids 2013 78 2 203 209 10.1016/j.steroids.2012.09.012 23178255
    [Google Scholar]
  132. Wang X.D. Su G.Y. Zhao C. Qu F.Z. Wang P. Zhao Y.Q. Anticancer activity and potential mechanisms of 1C, a ginseng saponin derivative, on prostate cancer cells. J. Ginseng Res. 2018 42 2 133 143 10.1016/j.jgr.2016.12.014 29719459
    [Google Scholar]
  133. Lin L. Zhao Y. Wang P. Li T. Liang Y. Chen Y. Meng X. Zhang Y. Su G. Amino acid derivatives of ginsenoside AD-2 induce HepG2 cell apoptosis by affecting the cytoskeleton. Molecules 2023 28 21 7400 10.3390/molecules28217400 37959819
    [Google Scholar]
  134. Ma L. Wang X. Li W. Miao D. Li Y. Lu J. Zhao Y. Synthesis and anti-cancer activity studies of dammarane-type triterpenoid derivatives. Eur. J. Med. Chem. 2020 187 111964 10.1016/j.ejmech.2019.111964 31862444
    [Google Scholar]
/content/journals/cmc/10.2174/0109298673373971250625075309
Loading
Participation of MDM2 in Pro-Apoptotic and Androgen Receptor-Degrading Potency of Selected Steroid and Terpenoid Derivatives
Bentham Science Publishers ; https://doi.org/10.2174/0109298673373971250625075309
/content/journals/cmc/10.2174/0109298673373971250625075309
/content/journals/cmc/10.2174/0109298673373971250625075309
Loading

Data & Media loading...


  • Article Type:     Review Article
Keywords: MDM2 ; prostate cancer cells ; Steroid derivatives ; terpenoid derivatives ; apoptosis ; androgen receptor degradation

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test