Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 1056 2022-11-02 08:47:36 |
2 format correct Meta information modification 1056 2022-11-02 08:59:44 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Khan, M.M.;  Torchilin, V.P. Mechanisms of Multidrug Resistance. Encyclopedia. Available online: https://encyclopedia.pub/entry/32436 (accessed on 20 June 2024).
Khan MM,  Torchilin VP. Mechanisms of Multidrug Resistance. Encyclopedia. Available at: https://encyclopedia.pub/entry/32436. Accessed June 20, 2024.
Khan, Muhammad Muzamil, Vladimir P. Torchilin. "Mechanisms of Multidrug Resistance" Encyclopedia, https://encyclopedia.pub/entry/32436 (accessed June 20, 2024).
Khan, M.M., & Torchilin, V.P. (2022, November 02). Mechanisms of Multidrug Resistance. In Encyclopedia. https://encyclopedia.pub/entry/32436
Khan, Muhammad Muzamil and Vladimir P. Torchilin. "Mechanisms of Multidrug Resistance." Encyclopedia. Web. 02 November, 2022.
Mechanisms of Multidrug Resistance
Edit
Drug resistance in cancer is a common cause of the poor response to chemotherapy and is associated with 90% of the mortality in cancer patients. The main causes of multidrug resistance (MDR) in cancer include the efflux of drugs, increased DNA repair capacity, genetic factors, and the increased metabolism of xenobiotics.
multidrug resistance (MDR) nanomedicines siRNA

1. Enhanced Efflux of Drugs

Drug resistance may be intrinsic or acquired and can be due to genetic factors, growth factors, the increased efflux of drugs, DNA repair, and the metabolism of xenobiotics. The strategies used to combat drug resistance include the nanomedicine-based targeted delivery of drugs and genes using different nanocarriers such as gold nanoparticles, peptide-modified nanoparticles, as well as biomimetic and responsive nanoparticles that help to deliver payload at targeted tumor sites and overcome resistance. Gene therapy in combination with chemotherapy aids in this respect. 

The enhanced efflux of chemotherapeutic agents resulting in lower intracellular drug concentration is one of the major causes of chemotherapeutic resistance [1]. Trans-membrane transporters that are responsible for drug efflux are mainly from the ABC transporter subfamily. There are 48 ABC genes classified into 7 subfamilies [2]. ATP-binding cassette (ABC) proteins such as P-glycoprotein (P-gp) are present on the surface of the cell membrane and are responsible for the absorption and excretion of a variety of chemical compounds. P-gp is highly overexpressed on the endothelial cell surface and leads to reduced drug penetration at the specific tumor site. P-gp can efflux a variety of anticancer agents, including anthracyclines, taxanes, and vinca alkaloids, to decrease the intracellular drug concentration [3]. A correlation between the overexpression of P-gp and increased resistance is particularly associated with paclitaxel, doxorubicin, vinblastine, etoposide, and olaparib [4][5]. In some types of hematological cancer, an initial low expression and then a dramatic increase in the level of P-gp (ABCB1) after chemotherapy has been observed [6]. ABCG2 is mainly involved in drug efflux in breast tumor resistance. It can transport both cationic and anionic drugs including chemotherapeutic agents and imatinib [7]. The efflux of drugs can also be mediated by extracellular vesicles (EVs), MRP1, and BCRP proteins. The functionality of efflux pump also depends on the composition and characteristics of the plasma membrane [8].

2. Genetic Factors

Certain genetic factors also contribute to chemotherapeutic resistance such as gene mutation, amplification, and epigenetic alterations.

2.1. Gene Mutations

Gene mutations mostly occur in tumor cells and are one of the major causes of chemotherapeutic resistance and poor treatment response. The basis for the development of MDR in cancer cells is their aneuploidy nature [9]. During the process of mitosis, the reassortment of chromosomes can lead to the loss of drug-sensitive genes with the resultant loss of chemotherapeutic resistance. By contrast, normal cells that do not lose or gain a chromosome retain their drug sensitivity [10]. Mutation in TP53 in cancer cells is a well-known biomarker for tumorigenesis. TP53 is responsible for regulating the cell cycle and inducing apoptosis in cases of genotoxic stress during the process of replication. Mutation in TP53 genes also leads to the loss of tumor-suppressive activities [10]. Similarly, mutations in BCR-ABL genes associated with drug-binding regions lead to resistance in chronic myeloid leukemia (CML) [11]. Some studies support a correlation between the reactivation of BCR-ABL genes and remission of CML [12].

2.2. Amplifications

Some chemotherapeutic agents such as methotrexate act by inhibiting key enzymes such as dihydrofolate reductase that control cell proliferation. A few types of cancer such as leukemia overcome this inhibition by enhancing the transcription of genes that encode the enzyme. This process is related to the synthesis of a specific region of a chromosome, and these amplified sequences are identified with double chromosomes. This results in the increased production of enzymes, and drug treatment strategies are not able to inhibit these enzymes, leading to reduced therapeutic activity [13]. The amplification of human epidermal growth factor receptor-2 (HER-2) leads to modification in a variety of genes and increases chemotherapeutic resistance to anti-HER-2 drugs [14].

2.3. Epigenetic Alterations

Epigenetic alterations also contribute to chemotherapeutic resistance. Epigenetic alterations include histone modification, DNA methylation, non-coding RNA-related alterations, and chromatin remodeling [15]. DNA hypermethylation or hypomethylation is a potential factor contributing to cancer drug resistance. During tumorigenesis, the epigenome undergoes some alterations including the loss of DNA methylation, histone modification, and changes in miRNA expression [16][17]. The demethylation of the ABCB1 gene results in the decreased accumulation of chemotherapeutic agents in cancer cells. Epigenetic alterations may also affect DNA repair systems. Epigenetic changes related to miRNAs play a key role in the development of chemotherapeutic resistance in cancer cells. Studies have shown that miRNA affects the sensitivity of cancer cells to anticancer drugs through epigenetic changes [18].

3. Growth Factors

The results of various studies indicate an association between inflammation and cancer. Chronic inflammatory responses lead to tumor invasion. There is increased production of interleukin (IL-4, IL-6, and IL-8) and growth factors in MDR tumors compared with drug-sensitive cancers [19][20]. IL-6 can affect different biological processes such as cell growth and death by increasing the expression of the ABCB1 gene. There is convincing evidence of a correlation between the presence of IL-6 in tumor stroma and the MDR of gastric tumors [21]. The enhanced activity of protein kinase-C and extracellular matrix (ECM) in breast cancer is associated with increased resistance to chemotherapy [22][23].

4. Increased DNA Repair

Tumor cells also develop resistance to various chemotherapeutic drugs by increasing their ability to repair DNA damage. DNA repair endonuclease XPF and DNA excision repair protein ERCC-1 are essential for the repair of DNA damage induced by platinum-based agents [24]. There is a correlation between the increased expression of XPF and ERCC-1 and tumor resistance to cisplatin. Cisplatin and 5-fluorouracil both kill tumor cells by inducing DNA damage. Some genes involved in DNA repair mechanisms such as FEN1 and FANCG are reported to be overexpressed in 5-FU-resistant colon cancers [25].

5. Elevated Metabolism of Xenobiotics

Some enzymes responsible for drug metabolism can contribute to chemotherapeutic resistance. Drug-metabolizing enzymes are an essential part of phase-I and phase-II metabolism. Cytochromes P450 are key enzymes responsible for the metabolism of a variety of drugs. An increased expression of CYP1B1 has been observed in some cancer cells that modify the biotransformation of paclitaxel, docetaxel, and flutamide [26]. An increased expression of the CYP2A6 enzyme, which is involved in the metabolism of cyclophosphamide and 5-fluorouracil, has been observed in breast cancer tissues. The overexpression of CYP1B1 and CYP2A7 in different cancers is related to increased resistance to different chemotherapeutic agents [27].

References

  1. Alfarouk, K.O.; Stock, C.-M.; Taylor, S.; Walsh, M.; Muddathir, A.K.; Verduzco, D.; Bashir, A.H.; Mohammed, O.Y.; Elhassan, G.O.; Harguindey, S. Resistance to cancer chemotherapy: Failure in drug response from ADME to P-gp. Cancer Cell Int. 2015, 15, 71.
  2. Wilkens, S. Structure and mechanism of ABC transporters. F1000prime Rep. 2015, 7, 14.
  3. Wang, J.; Seebacher, N.; Shi, H.; Kan, Q.; Duan, Z. Novel strategies to prevent the development of multidrug resistance (MDR) in cancer. Oncotarget 2017, 8, 84559.
  4. Satake, K.; Tsukamoto, M.; Mitani, Y.; Regasini, L.O.; da Silva Bolzani, V.; Efferth, T.; Nakagawa, H. Human ABCB1 confers cells resistance to cytotoxic guanidine alkaloids from Pterogyne nitens. Bio-Med. Mater. Eng. 2015, 25, 249–256.
  5. Lal, S.; Wong, Z.W.; Sandanaraj, E.; Xiang, X.; Ang, P.C.S.; Lee, E.J.; Chowbay, B. Influence of ABCB1 and ABCG2 polymorphisms on doxorubicin disposition in Asian breast cancer patients. Cancer Sci. 2008, 99, 816–823.
  6. Peng, X.-X.; Tiwari, A.K.; Wu, H.-C.; Chen, Z.-S. Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells. Chin. J. Cancer 2012, 31, 110.
  7. Mao, Q.; Unadkat, J.D. Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport—An update. AAPS J. 2015, 17, 65–82.
  8. Assaraf, Y.G.; Brozovic, A.; Gonçalves, A.C.; Jurkovicova, D.; Linē, A.; Machuqueiro, M.; Saponara, S.; Sarmento-Ribeiro, A.B.; Xavier, C.P.; Vasconcelos, M.H. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resist. Updates 2019, 46, 100645.
  9. Duesberg, P.; Stindl, R.; Hehlmann, R. Origin of multidrug resistance in cells with and without multidrug resistance genes: Chromosome reassortments catalyzed by aneuploidy. Proc. Natl. Acad. Sci. USA 2001, 98, 11283–11288.
  10. Mantovani, F.; Collavin, L.; Del Sal, G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ. 2019, 26, 199–212.
  11. Chandrasekhar, C.; Kumar, P.S.; Sarma, P.V.G.K. Novel mutations in the kinase domain of BCR-ABL gene causing imatinib resistance in chronic myeloid leukemia patients. Sci. Rep. 2019, 9, 2412.
  12. Shih, Y.-C.T.; Cortes, J.E.; Kantarjian, H.M. Treatment value of second-generation BCR-ABL1 tyrosine kinase inhibitors compared with imatinib to achieve treatment-free remission in patients with chronic myeloid leukaemia: A modelling study. Lancet Haematol. 2019, 6, e398–e408.
  13. Mansoori, B.; Mohammadi, A.; Davudian, S.; Shirjang, S.; Baradaran, B. The different mechanisms of cancer drug resistance: A brief review. Adv. Pharm. Bull. 2017, 7, 339.
  14. Wahdan-Alaswad, R.; Liu, B.; Thor, A.D. Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer: Opportunities to overcome a difficult problem. Cancer Drug Resist. 2020, 3, 179–198.
  15. Ohata, Y.; Shimada, S.; Akiyama, Y.; Mogushi, K.; Nakao, K.; Matsumura, S.; Aihara, A.; Mitsunori, Y.; Ban, D.; Ochiai, T. Acquired resistance with epigenetic alterations under long-term antiangiogenic therapy for hepatocellular carcinoma. Mol. Cancer Ther. 2017, 16, 1155–1165.
  16. Zhao, Z.; Shilatifard, A. Epigenetic modifications of histones in cancer. Genome Biol. 2019, 20, 245.
  17. Mohammad, H.P.; Barbash, O.; Creasy, C.L. Targeting epigenetic modifications in cancer therapy: Erasing the roadmap to cancer. Nat. Med. 2019, 25, 403–418.
  18. Si, W.; Shen, J.; Zheng, H.; Fan, W. The role and mechanisms of action of microRNAs in cancer drug resistance. Clin. Epigenet. 2019, 11, 25.
  19. Setrerrahmane, S.; Xu, H. Tumor-related interleukins: Old validated targets for new anti-cancer drug development. Mol. Cancer 2017, 16, 153.
  20. Conze, D.; Weiss, L.; Regen, P.S.; Bhushan, A.; Weaver, D.; Johnson, P.; Rincón, M. Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Res. 2001, 61, 8851–8858.
  21. Ham, I.-H.; Oh, H.J.; Jin, H.; Bae, C.A.; Jeon, S.-M.; Choi, K.S.; Son, S.-Y.; Han, S.-U.; Brekken, R.A.; Lee, D. Targeting interleukin-6 as a strategy to overcome stroma-induced resistance to chemotherapy in gastric cancer. Mol. Cancer 2019, 18, 68.
  22. Singh, R.K.; Kumar, S.; Gautam, P.K.; Tomar, M.S.; Verma, P.K.; Singh, S.P.; Acharya, A. Protein kinase C-α and the regulation of diverse cell responses. Biomol. Concepts 2017, 8, 143–153.
  23. Jena, M.K.; Janjanam, J. Role of extracellular matrix in breast cancer development: A brief update. F1000Research 2018, 7, 274.
  24. Gentile, F.; Elmenoufy, A.H.; Ciniero, G.; Jay, D.; Karimi-Busheri, F.; Barakat, K.H.; Weinfeld, M.; West, F.G.; Tuszynski, J.A. Computer-aided drug design of small molecule inhibitors of the ERCC1-XPF protein–protein interaction. Chem. Biol. Drug Des. 2020, 95, 460–471.
  25. Wang, X.; Zhang, H.; Chen, X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resist. 2019, 2, 141–160.
  26. Pathania, S.; Bhatia, R.; Baldi, A.; Singh, R.; Rawal, R.K. Drug metabolizing enzymes and their inhibitors’ role in cancer resistance. Biomed. Pharmacother. 2018, 105, 53–65.
  27. Li, Y.; Steppi, A.; Zhou, Y.; Mao, F.; Miller, P.C.; He, M.M.; Zhao, T.; Sun, Q.; Zhang, J. Tumoral expression of drug and xenobiotic metabolizing enzymes in breast cancer patients of different ethnicities with implications to personalized medicine. Sci. Rep. 2017, 7, 4747.
More
Information
Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : ,
View Times: 257
Revisions: 2 times (View History)
Update Date: 02 Nov 2022
1000/1000
Video Production Service