Doxorubicin-Based Hybrid Compounds as Potential Anticancer Agents: A Review
Abstract
:1. Introduction
2. Side Effects Associated with Doxorubicin
2.1. Doxorubicin Mechanism of Action
2.2. Doxorubicin Mechanism of Resistance
2.3. Possible Solution to Overcome Doxorubicin Negative Effects
3. Anticancer Activity of Doxorubicin and Its Derivatives
3.1. Cholesteryl-Doxorubicin Derivatives
3.2. Doxorubicin-Fatty Acyl Derivatives
3.3. Doxorubicin-Hydrazone Derivatives
3.4. Doxorubicin Hybrid Containing Compounds with Antioxidant Activity
3.5. Formamidino-Doxorubicin Derivatives
3.6. Dexamethasone-Doxorubicin Derivative
3.7. Doxorubicin Derivative Containing Arimetamycin Scaffolds
3.8. Photoresponsive-Doxorubicin Hybrid
3.9. Steroidal Anti-Estrogen−Doxorubicin Bioconjugate
3.10. Doxorubicin Computational Work
4. Future Perspectives and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Sritharan, S.; Sivalingam, N. A comprehensive review on time-tested anticancer drug doxorubicin. Life Sci. 2021, 278, 119527. [Google Scholar] [CrossRef] [PubMed]
- Tacar, O.; Sriamornsak, P.; Dass, C.R. Doxorubicin: An update on anticancer molecular action, toxicity and novel drug delivery systems. J. Pharm. Pharmacol. 2013, 65, 157–170. [Google Scholar] [CrossRef] [PubMed]
- Sung, H.; Ferlat, J.; Rebecca, M.E.; Siegel, M.P.H.; Laversanne, M.; Soaerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. Canc. J. Clin. 2021, 74, 209–249. [Google Scholar] [CrossRef] [PubMed]
- Wilson, B.E.; Jacob, S.; Yap, M.L.; Ferlay, J.; Bray, F.; Barton, M.B. Estimates of global chemotherapy demands and corresponding physician workforce requirements for 2018 and 2040: A population-based study. Lancet Oncol. 2019, 20, 769–780. [Google Scholar] [CrossRef]
- Aderibigbe, B.A.; Peter, S. Ferrocene-Based Compounds with Antimalaria/Anticancer Activity. Molecules 2019, 24, 3604. [Google Scholar] [CrossRef] [Green Version]
- International Agency for Research on Cancer. Latest Global Cancer Data: Cancer Burden Rises to 18.1 Million New Cases and 9.6 Million Cancer Deaths in 2018; International Agency for Research on Cancer: Lyon, France, 2018. [Google Scholar]
- Chen, C.; Lu, L.; Yan, S.; Yi, H.; Yao, H.; Wu, D.; He, G.; Tao, X.; Deng, X. Autophagy and Doxorubicin resistance in cancer. Anti-Cancer Drugs. 2018, 29, 1–9. [Google Scholar] [CrossRef]
- Moiseeva, A.A. Anthracycline Derivatives and Their Anticancer Activity. Ineos Open. 2019, 2, 9–18. [Google Scholar] [CrossRef]
- Damodar, G.; Smitha, T.; Gopinath, S.; Vijayakumar, S.; Rao, Y.A. An evaluation of hepatotoxicity in breast cancer patients receiving injection Doxorubicin. Ann. Med. Health Sci. Res. 2014, 4, 74–79. [Google Scholar] [CrossRef]
- Chhikara, B.S.; Mandal, D.; Parang, K. Synthesis, anticancer activities, and cellular uptake studies of lipophilic derivatives of doxorubicin succinate. J. Med Chem. 2012, 55, 1500–1510. [Google Scholar] [CrossRef]
- Hanušová, V.; Boušová, I.; Skálová, L. Possibilities to increase the effectiveness of doxorubicin in cancer cells killing. Drug Metab. Rev. 2011, 43, 540–557. [Google Scholar] [CrossRef]
- Mohan, U.P.; Tirupathi Pichiah, P.B.; Iqbal, S.T.A.; Arunachalam, S. Mechanisms of doxorubicin-mediated reproductive toxicity—A review. Reprod. Toxicol. 2021, 102, 80–89. [Google Scholar] [CrossRef] [PubMed]
- Van der Zanden, S.Y.; Qiao, X.; Neefjes, J. New insights into the activities and toxicities of the old anticancer drug doxorubicin. FEBS J. 2020, 288, 6095–6111. [Google Scholar] [CrossRef] [PubMed]
- Silva, R.C.; Britto, D.M.C.; de Fátima Pereira, W.; Brito-Melo, G.E.A.; Machado, C.T.; Pedreira, M.M. Effect of short-and medium-term toxicity of doxorubicin on spermatogenesis in adult Wistar rats. Reprod. Biol. 2018, 18, 169–176. [Google Scholar] [CrossRef] [PubMed]
- Çeribas, A.O.; Sakin, F.; Türk, G.; Sönmez, M.; Atessahin, A. Impact of ellagic acid on adriamycin-induced testicular histopathological lesions, apoptosis, lipid peroxidation and sperm damages. Exp. Toxicol. Pathol. 2012, 64, 717–724. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Abdelaziz, M.H.; Salah EL-Din, E.Y.; El-Dakdoky, M.H.; Ahmed, T.A. The impact of mesenchymal stem cells on doxorubicin-induced testicular toxicity and progeny outcome of male prepubertal rats. Birth Defects Res. 2019, 111, 906–919. [Google Scholar] [CrossRef]
- Salem, E.A.; Salem, N.A.; Hellstrom, W.J. Therapeutic effect of ozone and rutin on adriamycin-induced testicular toxicity in an experimental rat model. Andrologia 2017, 49, e12603. [Google Scholar] [CrossRef]
- Jukkala, A.M.; Meneses, K.M. Preserving fertility in young women diagnosed with breast Cancer. Oncology 2009, 23, 36–38. [Google Scholar]
- Zhang, T.; Yan, D.; Yang, Y.; Ma, A.; Li, L.; Wang, Z.; Pan, Q.; Sun, Z. The comparison of animal models for premature ovarian failure established by several different source of inducers. Regul. Toxicol. Pharmacol. 2016, 81, 223–232. [Google Scholar] [CrossRef]
- Pugazhendhi, A.; Edison, T.N.J.I.; Velmurugan, B.K.; Jacob, A.J.; Karuppusamy, I. Toxicity of Doxorubicin (Dox) to different experimental organ systems. Life Sci. 2018, 200, 26–30. [Google Scholar] [CrossRef]
- Siswanto, S.; Arozal, W.; Juniantito, V.; Grace, A.; Agustini, F.D.; Nafrialdi. The effect of mangiferin against brain damage caused by oxidative stress and inflammation in- duced by doxorubicin. HAYATI J. Biosci. 2016, 23, 51–55. [Google Scholar] [CrossRef] [Green Version]
- Oleaga, C.; Bernabini, C.; Smith, A.S.; Srinivasan, B.; Jackson, M.; McLamb, W.; Platt, V.; Bridges, R.; Cai, Y.; Santhanam, N.; et al. Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci. Rep. 2016, 6, 20030. [Google Scholar] [CrossRef] [PubMed]
- Shivakumar, P.; Rani, M.U.; Reddy, A.G.; Anjaneyulu, Y. A study on the toxic effects of doxorubicin on the histology of certain organs. Toxicol. Int. 2012, 19, 241–244. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Carvalho, C.; Santos, R.X.; Cardoso, S.; Correia, S.; Oliveira, P.J.; Santos, M.S.; Moreira, P.I. Doxorubicin: The Good, the Bad and the Ugly Effect. Curr. Med. Chem. 2009, 16, 3267–3285. [Google Scholar] [CrossRef] [PubMed]
- Jawad, B.; Poudel, L.; Podgornik, R.; Steinmetz, N.F.; Ching, W. Molecular mechanism and binding free energy of doxorubicin intercalation in DNA. Phys. Chem. Chem. Phys. 2019, 21, 3877–3893. [Google Scholar] [CrossRef]
- Rivankar, S. An overview of doxorubicin formulations in cancer therapy. J. Cancer Res. Ther. 2014, 10, 853–858. [Google Scholar] [CrossRef]
- Denel-Bobrowska, M.; Marczak, A. Structural modifications in the sugar moiety as a key to improving the anticancer effectiveness of doxorubicin. Life Sci. 2017, 178, 1–8. [Google Scholar] [CrossRef]
- Vendramin, R.; Katopodi, V.; Cinque, S.; Konnova, A.; Knezevic, Z.; Adnane, S.; Verheyden, Y.; Karras, P.; Demesmaeker, E.; Bosisio, F.M.; et al. Activation of the Integrated Stress Response in drug-tolerant melanoma cells confers vulnerability to mitoribosome-targeting antibiotics. J. Exp. Med. 2020, 218, e20210571. [Google Scholar] [CrossRef]
- Lovitt, C.J.; Shelper, T.B.; Avery, V.M. Doxorubicin resistance in breast cancer cells is mediated by extracellular matrix proteins. BMC Cancer 2018, 18, 41. [Google Scholar] [CrossRef] [Green Version]
- Cox, J.; Weinman, S. Mechanisms of doxorubicin resistance in hepatocellular carcinoma. Hepatic Oncol. 2016, 3, 57–59. [Google Scholar] [CrossRef]
- Choi, J.S.; Doh, K.O.; Kim, B.K.; Seu, Y.B. Synthesis of cholesteryl doxorubicin and its anti-cancer activity. Bioorg. Med. Chem. 2017, 27, 723–728. [Google Scholar] [CrossRef]
- Chhikara, B.S.; St Jean, N.; Mandal, D.; Kumar, A.; Parang, K. Fatty-acyl amide derivatives of doxorubicin: Synthesis and in vitro anticancer activities. Eur. J. Med. Chem. 2011, 46, 2037. [Google Scholar] [CrossRef] [PubMed]
- Fujiwara, S.; Amisaki, T. Fatty acid binding to serum albumin: Molecular simulation approaches. Biochim. Biophys. Acta 2013, 1830, 5427–5434. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lim, S.I.; Mizuta, Y.; Takasu, A.; Hahn, Y.S.; Kim, Y.H.; Kwon, I. Site-specific fatty acid-conjugation to prolong protein half-life in vivo. J. Control. Release 2013, 170, 219–225. [Google Scholar] [CrossRef] [Green Version]
- Kratz, F.; Elsadek, B. Clinical impact of serum proteins on drug delivery. J. Control. Release 2012, 161, 429–445. [Google Scholar] [CrossRef] [PubMed]
- Merendino, N.; Costantini, L.; Manzi, L.; Molinari, R.; D’Eliseo, D.; Velotti, F. Dietary omega-3 polyunsaturated fatty acid DHA: A potential adjuvant in the treatment of cancer. BioMed Res. Int. 2013, 2013, 310186. [Google Scholar] [CrossRef] [Green Version]
- Kuan, C.Y.; Walker, T.H.; Luo, P.G.; Chen, C.F. Long-chain polyunsaturated fatty acids promote paclitaxel cytotoxicity via inhibition of the MDR1 gene in the human colon cancer Caco-2 cell line. J. Am. Coll. Nutr. 2011, 30, 265–273. [Google Scholar] [CrossRef] [PubMed]
- Siddiqui, R.A.; Harvey, K.A.; Xu, Z.; Bammerlin, E.M.; Walker, C.; Altenburg, J.D. Docosahexaenoic acid: A natural powerful adjuvant that improves efficacy for anticancer treatment with no adverse effects. BioFactors 2011, 37, 399–412. [Google Scholar] [CrossRef] [PubMed]
- Effenberger, K.; Breyer, S.; Schobert, R. Modulation of doxorubicin activity in cancer cells by conjugation with fatty acyl and terpenyl hydrazones. Eur. J. Med. Chem. 2010, 45, 1947–1954. [Google Scholar] [CrossRef]
- Effenberger, K.; Breyer, S.; Ocker, M.; Schobert, R. New doxorubicin N-acyl hydrazones with improved efficacy and cell line specificity show modes of action different from the parent drug. Int. J. Clin. Pharmacol. Ther. 2010, 48, 485–486. [Google Scholar] [CrossRef]
- Liang, C.H.; Ye, W.L.; Zhu, C.L.; Na, R.; Cheng, Y.; Cui, H.; Liu, D.Z.; Yang, Z.F.; Zhou, S.Y. Synthesis of doxorubicin α-linolenic acid conjugate and evaluation of its antitumor activity. Mol. Pharm. 2014, 2014, 1378–1390. [Google Scholar] [CrossRef]
- Mielczarek-Puta, M.; Struga, M.; Roszkowski, P. Synthesis and anticancer effects of conjugates of doxorubicin and unsaturated fatty acids (LNA and DHA). Med. Chem. Res. 2019, 28, 2153–2164. [Google Scholar] [CrossRef] [Green Version]
- Graeser, R.; Esser, N.; Unger, H.; Fichtner, I.; Zhu, A.; Unger, C.; Kratz, F. INNO-206, the (6-maleimidocaproyl hydrazone derivative of doxorubicin), shows superior antitumor efficacy compared to doxorubicin in different tumor xenograft models and in an orthotopic pancreas carcinoma model. Investig. New Drugs 2010, 28, 14–19. [Google Scholar] [CrossRef] [PubMed]
- Chegaev, K.; Riganti, C.; Rolando, B.; Lazzarato, L.; Gazzano, E.; Guglielmo, S.; Ghigo, D.; Fruttero, R.; Gasco, A. Doxorubicin-antioxidant co-drugs. Bioorg. Med. Chem. Lett. 2013, 2013, 5307–5310. [Google Scholar] [CrossRef]
- Alrushaid, S.; Zhao, Y.; Sayre, C.L.; Maayah, Z.H.; Laird Forrest, M.; Senadheera, S.N.; Chaboyer, K.; Anderson, H.D.; El-Kadi, A.O.S.; Davies, N.M. Mechanistically elucidating the in vitro safety and efficacy of a novel doxorubicin derivative. Drug Deliv. Transl. Res. 2017, 7, 582–597. [Google Scholar] [CrossRef] [PubMed]
- Marczak, A.; Denel-Bobrowska, M.; Rogalska, A.; Łukawska, M.; Oszczapowicz, I. Cytotoxicity and induction of apoptosis by formamidinodoxorubicins in comparison to doxorubicin in human ovarian adenocarcinoma cells. Environ. Toxicol. Pharmacol. 2015, 39, 369–383. [Google Scholar] [CrossRef]
- Bogason, A.; Bhuiyan, H.; Masquelier, M.; Paul, C.; Gruber, A.; Vitols, S. Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response. Eur. J. Clin. Pharmacol. 2009, 65, 1179–1186. [Google Scholar] [CrossRef]
- Stojak, M.; Mazur, L.; Opydo-Chanek, M.; Lukawska, M.; Oszczapowicz, I. In vitro induction of apoptosis and necrosis by new derivatives of daunorubicin. Anticancer Res. 2013, 33, 4439–4443. [Google Scholar]
- Ouyang, Z.X.; Li, X.A. Inhibitory effects of tamoxifen and doxorubicin, alone and in combination, on the proliferation of the MG63 human osteosarcoma cell line. Oncol. Lett. 2013, 6, 970–976. [Google Scholar] [CrossRef] [PubMed]
- Gajek, A.; Denel, M.; Bukowska, B.; Rogalska, A.; Marczak, A. Pro-apoptotic activity of new analog of anthracyclines--WP 631 in advanced ovarian cancer cell line. Toxicol. Vitr. 2014, 28, 273–281. [Google Scholar] [CrossRef]
- Szwed, M.; Laroche-Clary, A.; Robert, J.; Jozwiak, Z. Induction of apoptosis by doxorubicin-transferrin conjugate compared to free doxorubicin in the human leukemia cell lines. Chem. Biol. Interact. 2014, 220, 140–148. [Google Scholar] [CrossRef]
- Chaikomon, K.; Chattong, S.; Chaiya, T.; Tiwawech, D.; Sritana-Anant, Y.; Sereemaspun, A.; Manotham, K. Doxorubicin-conjugated dexamethasone induced MCF-7 apoptosis without entering the nucleus and able to overcome MDR-1-induced resistance. Drug Des. Dev. Ther. 2018, 12, 2361–2369. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huseman, E.D.; Byl, J.A.; Chapp, S.M.; Schley, N.D.; Osheroff, N.; Townsend, S.D. Synthesis and Cytotoxic Evaluation of Arimetamycin A and Its Daunorubicin and Doxorubicin Hybrids. ACS Cent. Sci. 2021, 7, 1327–1337. [Google Scholar] [CrossRef] [PubMed]
- Wander, D.P.A.; van der Zanden, S.Y.; van der Marel, G.A.; Overkleeft, H.S.; Neefjes, J.; Codée, J.D.C. Doxorubicin and Aclarubicin: Shuffling Anthracycline Glycans for Improved Anticancer Agents. J. Med. Chem. 2020, 63, 12814–12829. [Google Scholar] [CrossRef] [PubMed]
- Liu, W.; Liang, L.; Zhao, L.; Tan, H.; Wu, J.; Qin, Q.; Gou, X.; Sun, X. Synthesis and characterization of a photoresponsive doxorubicin/combretastatin A4 hybrid prodrug. Bioorg. Med. Chem. Lett. 2019, 29, 487–490. [Google Scholar] [CrossRef] [PubMed]
- Dao, K.L.; Sawant, R.R.; Hendricks, J.A.; Ronga, V.; Torchilin, V.P.; Hanson, R.N. Design, synthesis, and initial biological evaluation of a steroidal anti-estrogen–doxorubicin bioconjugate for targeting estrogen receptor-positive breast cancer cells. Bioconjugate Chem. 2012, 18, 23–785. [Google Scholar] [CrossRef] [Green Version]
- Mahdavi, M.; Rahmani, F.; Nouranian, S. Molecular simulation of pH-dependent diffusion, loading, and release of doxorubicin in graphene and graphene oxide drug delivery systems. J. Mater. Chem. B 2016, 4, 7441–7451. [Google Scholar] [CrossRef]
- Khoshoei, A.; Ghasemy, E.; Poustchi, F.; Shahbazi, M.A.; Maleki, R. Engineering the pH-Sensitivity of the Graphene and Carbon Nanotube Based Nanomedicines in Smart Cancer Therapy by Grafting Trimetyl Chitosan. Pharm. Res. 2020, 37, 160. [Google Scholar] [CrossRef]
- Maleki, R.; Khedri, M.; Malekahmadi, D.; Mohaghegh, S.; Jahromi, A.M.; Shahbazi, M.A. Simultaneous doxorubicin encapsulation and in-situ microfluidic micellization of bio-targeted polymeric nanohybrids using dichalcogenide monolayers: A molecular in-silico study. Mater. Today Commun. 2021, 26, 101948. [Google Scholar] [CrossRef]
- Turky, A.; Bayoumi, A.H.; Sherbiny, F.F.; El-Adl, K.; Abulkhair, H.S. Unravelling the anticancer potency of 1,2,4-triazole-N-arylamide hybrids through inhibition of STAT3: Synthesis and in silico mechanistic studies. Mol. Divers. 2021, 25, 403–420. [Google Scholar] [CrossRef]
- Hidayat, A.T.; Yusuf, M.; Bachti, H.H.; Diantini, A.; Zainuddin, A. Computational model of doxorubicin conjugate with docosahexaenoic acid and integrin αv β3 ligand for anticancer. J. Appl. Pharm. Sci. 2018, 8, 1–6. [Google Scholar] [CrossRef] [Green Version]
- Alves, A.C.; Magarkar, A.; Horta, M.; Lima, J.L.F.C.; Bunker, A.; Nunes, C.; Reis, S. Influence of doxorubicin on model cell membrane properties: Insights from in vitro and in silico studies. Sci. Rep. 2017, 7, 6343. [Google Scholar] [CrossRef] [PubMed] [Green Version]
IC50 (μM) | Compound 4 | Doxorubicin | Compound 5 |
---|---|---|---|
MCF 7 | 9.94 | 4.39 | 9.69 |
A549 | 11.22 | 11.62 | 8.03 |
MDA MB 231 | 21.60 | 14.66 | 16.35 |
HeLa | 27.88 | 7.18 | 8.03 |
IC50(μM) | Doxorubicin | Compound 10d |
---|---|---|
MDA-MB-231 | 4.3 ± 1.1 | 2.2 ± 0.7 |
MCF-7 | 3.6 ± 1.3 | 1.7 ± 0.3 |
HepG2 | 3.2 ± 0.7 | 1.3 ± 0.4 |
IC50 | doxorubicin | 15a | 15b | 15c | 15d | 15e |
---|---|---|---|---|---|---|
SKOV-3 | 352.79 ± 25.04 | 251.27 ± 19.3 | 112.30 ± 9.55 | 82.42 ± 8.47 | 112.48 ± 11.29 | 81.37 ± 32.49 |
Compound | Cancer Cell Lines | ||
---|---|---|---|
HCT116 | MDA-MB 231 | H69AR | |
17a | 40 | <30 | 30 |
Arimetamycin A | 250 | 320 | 90 |
17b | 330 | 970 | 1010 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Peter, S.; Alven, S.; Maseko, R.B.; Aderibigbe, B.A. Doxorubicin-Based Hybrid Compounds as Potential Anticancer Agents: A Review. Molecules 2022, 27, 4478. https://doi.org/10.3390/molecules27144478
Peter S, Alven S, Maseko RB, Aderibigbe BA. Doxorubicin-Based Hybrid Compounds as Potential Anticancer Agents: A Review. Molecules. 2022; 27(14):4478. https://doi.org/10.3390/molecules27144478
Chicago/Turabian StylePeter, Sijongesonke, Sibusiso Alven, Rejoice Bethusile Maseko, and Blessing Atim Aderibigbe. 2022. "Doxorubicin-Based Hybrid Compounds as Potential Anticancer Agents: A Review" Molecules 27, no. 14: 4478. https://doi.org/10.3390/molecules27144478
APA StylePeter, S., Alven, S., Maseko, R. B., & Aderibigbe, B. A. (2022). Doxorubicin-Based Hybrid Compounds as Potential Anticancer Agents: A Review. Molecules, 27(14), 4478. https://doi.org/10.3390/molecules27144478