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In vitro, in silico and in vivo screening of non-oncology drugs for repurposing in osteosarcoma

Yıl 2023, Cilt: 27 Sayı: 2, 712 - 721, 27.06.2025

Sujit Desai Arehalli Manjappa Preeti Khulbe Prafulla Choudharı , Popat Kumbhar

Öz

The first-line chemotherapy is associated with chief shortfalls such as non-specific distribution
causing severe dose-dependent toxicities and development of tumor resistance. The current preliminary
study aimed to identify the safe and effective non-oncology drugs as an alternative to toxic
chemotherapeutics to treat osteosarcoma, and overcome new drug’s shortage and development challenges.
The different category non-oncology drugs (alone and in combinations) were screened for in vitro
cytotoxicity behavior via MTT dye reduction assay and cell cycle arresting behavior using flow cytometer
against human osteosarcoma (Saos-2 and MG-63) cells. The molecular docking of selected therapeutics was
executed against cyclin-dependent kinase 1 (CDK1), cell cycle regulator overexpressed in cancer. The
identified combination was further tested for in vivo toxicities in rats at two different doses. The current
study revealed niclosamide (NSD), ketoconazole (KCZ), simvastatin (SVN) combination that causes
substantial cytotoxicity (IC50 values are in picomoles) at 1:1:3 molar ratio when compared to other molar
ratios. This combination has also caused substantial arrest of Saos-2 and MG-63 cells at S and G2/M phase.
Additionally, all three drugs demonstrated better interaction with CDK1 indicating anticancer potential via
inhibition of CDK1. Furthermore, the in vivo toxicity study revealed no significant changes in hematological
and biochemical parameters, body weights of rats, weights of vital organs, daily food and water intake, and
general behavior of rats. The obtained preliminary results revealed the potential application of this
combination on non-oncology drugs in the safe and effective treatment of osteosarcoma. However, further
in-depth studies are required before clinical application.

Anahtar Kelimeler

Drug repurposing osteosarcoma cytotoxicity molecular docking acute toxicity

Kaynakça

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394– 424. http://dx.doi.org/10.3322/caac.21492
  • Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012: Global Cancer Statistics, 2012. CA Cancer J Clin. 2015; 65(2): 87–108. http://dx.doi.org/10.3322/caac.21262
  • Eder J, Sedrani R, Wiesmann C. The discovery of first-in-class drugs: origins and evolution. Nat Rev Drug Discov. 2014; 13(8): 577–87. http://dx.doi.org/10.1038/nrd4336
  • Munos B. Lessons from 60 years of pharmaceutical innovation. Nat Rev Drug Discov. 2009; 8(12): 959–68. http://dx.doi.org/10.1038/nrd2961
  • Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D and Pirmohamed M. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019; 18(1): 41–58. http://dx.doi.org/10.1038/nrd.2018.168
  • Pantziarka P. Scientific advice - is drug repurposing missing a trick? Nat Rev ClinOncol. 2017; 14(8): 455–6. http://dx.doi.org/10.1038/nrclinonc.2017.69
  • Corsello SM, Bittker JA, Liu Z, Gould J, McCarren P, Hirschman JE, Johnston SE, Vrcic A, Wong B, Khan M, Asiedu J, Narayan R, Mader CC, Subramanian A, Golub TR. The Drug Repurposing Hub: a next-generation drug library and information resource. Nat Med. 2017; 23(4): 405–8. http://dx.doi.org/10.1038/nm.4306
  • Nosengo N. Can you teach old drugs new tricks? Nature. 2016; 534(7607): 314–6. http://dx.doi.org/10.1038/534314a
  • Clohessy JG, Pandolfi PP. Mouse hospital and co-clinical trial project--from bench to bedside. Nat Rev Clin Oncol. 2015; 12(8): 491–8. http://dx.doi.org/10.1038/nrclinonc.2015.62
  • Maxmen A. Busting the billion-dollar myth: how to slash the cost of drug development. Nature. 2016; 536(7617): 388–90. http://dx.doi.org/10.1038/536388a
  • Bertolini F, Sukhatme VP, Bouche G. Drug repurposing in oncology--patient and health systems opportunities. Nat Rev ClinOncol. 2015;12(12): 732–42. http://dx.doi.org/10.1038/nrclinonc.2015.169
  • Zhang Z, Zhou L, Xie N, Nice EC, Zhang T, Cui Y, Huang C. Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduct Target Ther. 2020; 5(1): 113. http://dx.doi.org/10.1038/s41392-020-00213-8
  • Lindsey BA, Markel JE, Kleinerman ES. Osteosarcoma overview. RheumatolTher. 2017; 4(1): 25–43. http://dx.doi.org/10.1007/s40744-016-0050-2
  • Cabrera-Andrade A, López-Cortés A, Jaramillo-Koupermann G, González-Díaz H, Pazos A, Munteanu CR, Perez- Castillo Y and Tejera E. A multi-objective approach for anti-osteosarcoma cancer agents discovery through drug repurposing. Pharmaceuticals (Basel). 2020; 13(11): 409. http://dx.doi.org/10.3390/ph13110409
  • Omer N, Le Deley M-C, Piperno-Neumann S, Marec-Berard P, Italiano A, Corradini N, Bellera C, Brugieres L and Gaspar N. Phase-II trials in osteosarcoma recurrences: A systematic review of past experience. Eur J Cancer. 2017; 75: 98–108. http://dx.doi.org/10.1016/j.ejca.2017.01.005
  • Harrison DJ, Geller DS, Gill JD, Lewis VO, Gorlick R. Current and future therapeutic approaches for osteosarcoma. Expert Rev Anticancer Ther. 2018; 18(1): 39–50. http://dx.doi.org/10.1080/14737140.2018.1413939
  • Kumbhar P, Kole K, Yadav T, Bhavar A, Waghmare P, Bhokare R, Manjappa A , Jha NK, Chelappan DK, Shinde S, Singh SK, Dua K, Salawi A, Disouza J and Patravale V. Drug repurposing: An emerging strategy in alleviating skin cancer. Eur J Pharmacol. 2022; 926(175031): 175031. http://dx.doi.org/10.1016/j.ejphar.2022.175031
  • Kumbhar P, Manjappa A, Shah R, Jha NK, Singh SK, Dua K, Disouza J and Patravale V. Inhalation delivery of repurposed drugs for lung cancer: Approaches, benefits and challenges. J Control Release. 2022; 341: 1–15. http://dx.doi.org/10.1016/j.jconrel.2021.11.015
  • Patil OB, Manjappa AS, Kumbhar PS, Bhosale SP, Disouza JI, Salawi A Sambamoorthy U. Development of stable self-nanoemulsifying composition and its nanoemulsions for improved oral delivery of non-oncology drugs against hepatic cancer. OpenNano. 2022; 7(100044): 100044. http://dx.doi.org/10.1016/j.onano.2022.100044
  • Kumbhar P, Kole K, Khadake V, Marale P, Manjappa A, Nadaf S, Jadhav R, Patil A, Singh SK, Dua K, Jha NK, Disouza J and Patravale V. Nanoparticulate drugs and vaccines: Breakthroughs and bottlenecks of repurposing in breast cancer. J Control Release. 2022; 349: 812–30. http://dx.doi.org/10.1016/j.jconrel.2022.07.039
  • Ding L, Cao J, Lin W, Chen H, Xiong X, Ao H, Yu M, Lin J and Cui Q. The roles of cyclin-dependent kinases in cell- cycle progression and therapeutic strategies in human breast cancer. Int J Mol Sci. 2020; 21(6): 1960. http://dx.doi.org/10.3390/ijms21061960
  • Quéméneur L, Gerland L-M, Flacher M, Ffrench M, Revillard J-P, Genestier L. Differential control of cell cycle, proliferation, and survival of primary T lymphocytes by purine and pyrimidine nucleotides. J Immunol. 2003;170(10): 4986–95. http://dx.doi.org/10.4049/jimmunol.170.10.4986
  • Izadi S, Nikkhoo A, Hojjat-Farsangi M, Namdar A, Azizi G, Mohammadi H, Yousefi M and Jadidi-Niaragh F. CDK1 in breast cancer: Implications for theranostic potential. Anticancer Agents Med Chem. 2020; 20(7): 758–67. http://dx.doi.org/10.2174/1871520620666200203125712
  • Li M, He F, Zhang Z, Xiang Z, Hu D. CDK1 serves as a potential prognostic biomarker and target for lung cancer. J Int Med Res. 2020; 48(2): 300060519897508. http://dx.doi.org/10.1177/0300060519897508
  • Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer [Internet]. 2009; 9(3): 153–66. http://dx.doi.org/10.1038/nrc2602
  • Sánchez-Díaz A, González I, Arellano M, Moreno S. The Cdk inhibitors p25rum1 and p40SIC1 are functional homologues that play similar roles in the regulation of the cell cycle in fission and budding yeast. J Cell Sci. 1998; 111 ( Pt 6):843–51. http://dx.doi.org/10.1242/jcs.111.6.843
  • Sambamoorthy U, Manjappa AS, Eswara BRM, Sanapala AK, Nagadeepthi N. Vitamin E oil incorporated liposomal melphalan and simvastatin: Approach to obtain improved physicochemical characteristics of hydrolysable melphalan and anticancer activity in combination with simvastatin against multiple myeloma. AAPS PharmSciTech. 2021; 23(1): 23. http://dx.doi.org/10.1208/s12249-021-02177-6
  • Manjappa AS, Kumbhar PS, Kasabe R, Diwate SK, Disouza JI. Ameliorated in vitro anticancer efficacy of methotrexate d-α-Tocopheryl polyethylene glycol 1000 succinate ester against breast cancer cells. Futur J Pharm Sci. 2019; 5(1). http://dx.doi.org/10.1186/s43094-019-0013-x
  • Bandgar SA, Jadhav NR, Manjappa AS. A remarkable in vitro cytotoxic, cell cycle arresting and proapoptotic characteristics of low-dose mixed micellar simvastatin combined with alendronate sodium. Drug Deliv Transl Res. 2020; 10(4): 1122–35. http://dx.doi.org/10.1007/s13346-020-00752-1
  • Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Methods Mol Biol. 2015; 1263: 243– 50. http://dx.doi.org/10.1007/978-1-4939-2269-7_19 Wikipedia contributors. Discovery Studio. Wikipedia, The Free Encyclopedia. 2021.
  • Unnam S, Manjappa AS, MuddanaEswara BR, Salawi A, Gunti P. Liposomal Melphalan: Approach to obtain improved plasma stability, pharmacokinetics, and in vitro and in vivo anticancer efficacy in combination with liposomal simvastatin against mouse RPMI-8226 multiple myeloma model. J Drug Deliv Sci Technol. 2022; 73(103479): 103479. http://dx.doi.org/10.1016/j.jddst.2022.103479

Yıl 2023, Cilt: 27 Sayı: 2, 712 - 721, 27.06.2025

Sujit Desai Arehalli Manjappa Preeti Khulbe Prafulla Choudharı , Popat Kumbhar

Öz

Kaynakça

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394– 424. http://dx.doi.org/10.3322/caac.21492
  • Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012: Global Cancer Statistics, 2012. CA Cancer J Clin. 2015; 65(2): 87–108. http://dx.doi.org/10.3322/caac.21262
  • Eder J, Sedrani R, Wiesmann C. The discovery of first-in-class drugs: origins and evolution. Nat Rev Drug Discov. 2014; 13(8): 577–87. http://dx.doi.org/10.1038/nrd4336
  • Munos B. Lessons from 60 years of pharmaceutical innovation. Nat Rev Drug Discov. 2009; 8(12): 959–68. http://dx.doi.org/10.1038/nrd2961
  • Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D and Pirmohamed M. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019; 18(1): 41–58. http://dx.doi.org/10.1038/nrd.2018.168
  • Pantziarka P. Scientific advice - is drug repurposing missing a trick? Nat Rev ClinOncol. 2017; 14(8): 455–6. http://dx.doi.org/10.1038/nrclinonc.2017.69
  • Corsello SM, Bittker JA, Liu Z, Gould J, McCarren P, Hirschman JE, Johnston SE, Vrcic A, Wong B, Khan M, Asiedu J, Narayan R, Mader CC, Subramanian A, Golub TR. The Drug Repurposing Hub: a next-generation drug library and information resource. Nat Med. 2017; 23(4): 405–8. http://dx.doi.org/10.1038/nm.4306
  • Nosengo N. Can you teach old drugs new tricks? Nature. 2016; 534(7607): 314–6. http://dx.doi.org/10.1038/534314a
  • Clohessy JG, Pandolfi PP. Mouse hospital and co-clinical trial project--from bench to bedside. Nat Rev Clin Oncol. 2015; 12(8): 491–8. http://dx.doi.org/10.1038/nrclinonc.2015.62
  • Maxmen A. Busting the billion-dollar myth: how to slash the cost of drug development. Nature. 2016; 536(7617): 388–90. http://dx.doi.org/10.1038/536388a
  • Bertolini F, Sukhatme VP, Bouche G. Drug repurposing in oncology--patient and health systems opportunities. Nat Rev ClinOncol. 2015;12(12): 732–42. http://dx.doi.org/10.1038/nrclinonc.2015.169
  • Zhang Z, Zhou L, Xie N, Nice EC, Zhang T, Cui Y, Huang C. Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduct Target Ther. 2020; 5(1): 113. http://dx.doi.org/10.1038/s41392-020-00213-8
  • Lindsey BA, Markel JE, Kleinerman ES. Osteosarcoma overview. RheumatolTher. 2017; 4(1): 25–43. http://dx.doi.org/10.1007/s40744-016-0050-2
  • Cabrera-Andrade A, López-Cortés A, Jaramillo-Koupermann G, González-Díaz H, Pazos A, Munteanu CR, Perez- Castillo Y and Tejera E. A multi-objective approach for anti-osteosarcoma cancer agents discovery through drug repurposing. Pharmaceuticals (Basel). 2020; 13(11): 409. http://dx.doi.org/10.3390/ph13110409
  • Omer N, Le Deley M-C, Piperno-Neumann S, Marec-Berard P, Italiano A, Corradini N, Bellera C, Brugieres L and Gaspar N. Phase-II trials in osteosarcoma recurrences: A systematic review of past experience. Eur J Cancer. 2017; 75: 98–108. http://dx.doi.org/10.1016/j.ejca.2017.01.005
  • Harrison DJ, Geller DS, Gill JD, Lewis VO, Gorlick R. Current and future therapeutic approaches for osteosarcoma. Expert Rev Anticancer Ther. 2018; 18(1): 39–50. http://dx.doi.org/10.1080/14737140.2018.1413939
  • Kumbhar P, Kole K, Yadav T, Bhavar A, Waghmare P, Bhokare R, Manjappa A , Jha NK, Chelappan DK, Shinde S, Singh SK, Dua K, Salawi A, Disouza J and Patravale V. Drug repurposing: An emerging strategy in alleviating skin cancer. Eur J Pharmacol. 2022; 926(175031): 175031. http://dx.doi.org/10.1016/j.ejphar.2022.175031
  • Kumbhar P, Manjappa A, Shah R, Jha NK, Singh SK, Dua K, Disouza J and Patravale V. Inhalation delivery of repurposed drugs for lung cancer: Approaches, benefits and challenges. J Control Release. 2022; 341: 1–15. http://dx.doi.org/10.1016/j.jconrel.2021.11.015
  • Patil OB, Manjappa AS, Kumbhar PS, Bhosale SP, Disouza JI, Salawi A Sambamoorthy U. Development of stable self-nanoemulsifying composition and its nanoemulsions for improved oral delivery of non-oncology drugs against hepatic cancer. OpenNano. 2022; 7(100044): 100044. http://dx.doi.org/10.1016/j.onano.2022.100044
  • Kumbhar P, Kole K, Khadake V, Marale P, Manjappa A, Nadaf S, Jadhav R, Patil A, Singh SK, Dua K, Jha NK, Disouza J and Patravale V. Nanoparticulate drugs and vaccines: Breakthroughs and bottlenecks of repurposing in breast cancer. J Control Release. 2022; 349: 812–30. http://dx.doi.org/10.1016/j.jconrel.2022.07.039
  • Ding L, Cao J, Lin W, Chen H, Xiong X, Ao H, Yu M, Lin J and Cui Q. The roles of cyclin-dependent kinases in cell- cycle progression and therapeutic strategies in human breast cancer. Int J Mol Sci. 2020; 21(6): 1960. http://dx.doi.org/10.3390/ijms21061960
  • Quéméneur L, Gerland L-M, Flacher M, Ffrench M, Revillard J-P, Genestier L. Differential control of cell cycle, proliferation, and survival of primary T lymphocytes by purine and pyrimidine nucleotides. J Immunol. 2003;170(10): 4986–95. http://dx.doi.org/10.4049/jimmunol.170.10.4986
  • Izadi S, Nikkhoo A, Hojjat-Farsangi M, Namdar A, Azizi G, Mohammadi H, Yousefi M and Jadidi-Niaragh F. CDK1 in breast cancer: Implications for theranostic potential. Anticancer Agents Med Chem. 2020; 20(7): 758–67. http://dx.doi.org/10.2174/1871520620666200203125712
  • Li M, He F, Zhang Z, Xiang Z, Hu D. CDK1 serves as a potential prognostic biomarker and target for lung cancer. J Int Med Res. 2020; 48(2): 300060519897508. http://dx.doi.org/10.1177/0300060519897508
  • Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer [Internet]. 2009; 9(3): 153–66. http://dx.doi.org/10.1038/nrc2602
  • Sánchez-Díaz A, González I, Arellano M, Moreno S. The Cdk inhibitors p25rum1 and p40SIC1 are functional homologues that play similar roles in the regulation of the cell cycle in fission and budding yeast. J Cell Sci. 1998; 111 ( Pt 6):843–51. http://dx.doi.org/10.1242/jcs.111.6.843
  • Sambamoorthy U, Manjappa AS, Eswara BRM, Sanapala AK, Nagadeepthi N. Vitamin E oil incorporated liposomal melphalan and simvastatin: Approach to obtain improved physicochemical characteristics of hydrolysable melphalan and anticancer activity in combination with simvastatin against multiple myeloma. AAPS PharmSciTech. 2021; 23(1): 23. http://dx.doi.org/10.1208/s12249-021-02177-6
  • Manjappa AS, Kumbhar PS, Kasabe R, Diwate SK, Disouza JI. Ameliorated in vitro anticancer efficacy of methotrexate d-α-Tocopheryl polyethylene glycol 1000 succinate ester against breast cancer cells. Futur J Pharm Sci. 2019; 5(1). http://dx.doi.org/10.1186/s43094-019-0013-x
  • Bandgar SA, Jadhav NR, Manjappa AS. A remarkable in vitro cytotoxic, cell cycle arresting and proapoptotic characteristics of low-dose mixed micellar simvastatin combined with alendronate sodium. Drug Deliv Transl Res. 2020; 10(4): 1122–35. http://dx.doi.org/10.1007/s13346-020-00752-1
  • Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Methods Mol Biol. 2015; 1263: 243– 50. http://dx.doi.org/10.1007/978-1-4939-2269-7_19 Wikipedia contributors. Discovery Studio. Wikipedia, The Free Encyclopedia. 2021.
  • Unnam S, Manjappa AS, MuddanaEswara BR, Salawi A, Gunti P. Liposomal Melphalan: Approach to obtain improved plasma stability, pharmacokinetics, and in vitro and in vivo anticancer efficacy in combination with liposomal simvastatin against mouse RPMI-8226 multiple myeloma model. J Drug Deliv Sci Technol. 2022; 73(103479): 103479. http://dx.doi.org/10.1016/j.jddst.2022.103479
Toplam 31 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Farmasotik Kimya
Bölüm Articles
Yazarlar

Sujit Desai 0000-0002-8339-2761

Arehalli Manjappa 0000-0002-8576-6608

Preeti Khulbe 0000-0001-9704-7494

Prafulla Choudharı 0000-0002-9137-3982

Popat Kumbhar 0000-0002-6753-239X

Yayımlanma Tarihi 27 Haziran 2025
Yayımlandığı Sayı Yıl 2023 Cilt: 27 Sayı: 2

Kaynak Göster

APA Desai, S., Manjappa, A., Khulbe, P., Choudharı, P., vd. (2025). In vitro, in silico and in vivo screening of non-oncology drugs for repurposing in osteosarcoma. Journal of Research in Pharmacy, 27(2), 712-721.
AMA Desai S, Manjappa A, Khulbe P, Choudharı P, Kumbhar P. In vitro, in silico and in vivo screening of non-oncology drugs for repurposing in osteosarcoma. J. Res. Pharm. Haziran 2025;27(2):712-721.
Chicago Desai, Sujit, Arehalli Manjappa, Preeti Khulbe, Prafulla Choudharı, ve Popat Kumbhar. “In Vitro, in Silico and in Vivo Screening of Non-Oncology Drugs for Repurposing in Osteosarcoma”. Journal of Research in Pharmacy 27, sy. 2 (Haziran 2025): 712-21.
EndNote Desai S, Manjappa A, Khulbe P, Choudharı P, Kumbhar P (01 Haziran 2025) In vitro, in silico and in vivo screening of non-oncology drugs for repurposing in osteosarcoma. Journal of Research in Pharmacy 27 2 712–721.
IEEE S. Desai, A. Manjappa, P. Khulbe, P. Choudharı, ve P. Kumbhar, “In vitro, in silico and in vivo screening of non-oncology drugs for repurposing in osteosarcoma”, J. Res. Pharm., c. 27, sy. 2, ss. 712–721, 2025.
ISNAD Desai, Sujit vd. “In Vitro, in Silico and in Vivo Screening of Non-Oncology Drugs for Repurposing in Osteosarcoma”. Journal of Research in Pharmacy 27/2 (Haziran 2025), 712-721.
JAMA Desai S, Manjappa A, Khulbe P, Choudharı P, Kumbhar P. In vitro, in silico and in vivo screening of non-oncology drugs for repurposing in osteosarcoma. J. Res. Pharm. 2025;27:712–721.
MLA Desai, Sujit vd. “In Vitro, in Silico and in Vivo Screening of Non-Oncology Drugs for Repurposing in Osteosarcoma”. Journal of Research in Pharmacy, c. 27, sy. 2, 2025, ss. 712-21.
Vancouver Desai S, Manjappa A, Khulbe P, Choudharı P, Kumbhar P. In vitro, in silico and in vivo screening of non-oncology drugs for repurposing in osteosarcoma. J. Res. Pharm. 2025;27(2):712-21.