The conformational modifications are rendered possible by formation of a transient double DNA break, followed by a DNA strand passage and eventually by relegation. DNA topoisomerase II-targeted drugs are anthracyclines, anthracenediones, epipodophyllotoxins, actinomycin D and amsacrines. The drugs involved in MDR due to alteration of topoisomerase II are essentially the same drugs involved in the Pmediated MDR, with the exception of Vinca alkaloids and taxanes [ 18 ]. In recent years, some genes involved in response to cell damage particularly DNA damage have also been investigated as possibly responsible for drug resistance.
Tumor cells which have mutant p53 are less sensitive to a large spectrum of drugs including doxorubicin, cisplatin and 5-fluorouracil [ 20 ]. Given the fact that p53 appears to be the gene that most frequently is altered in human malignancy, these considerations may be of extreme importance. This is a field in very rapid development, and it now appears clear that downstream genes may play an important role. This new understanding of the tumor biology opens up new therapeutic possibilities, including gene therapy.
With the advances in understanding the mechanisms of drug resistance, it appears more and more clear that within a given tumor there may well be multiple mechanisms in action. A large number of trials attempting to revert P-glycoprotein-mediated MDR have been performed. Many substances with drug-resistance-modifying capabilities are known. Although the mechanism of MDR reversal can be complex, nearly all reversal compounds are substrates of P-glycoprotein and compete with the cytotoxic drug for extrusion from the cell. The first of these substances to be tested was verapamil, which unfortunately was found to be extremely cardiotoxic at doses which give patients plasma concentrations necessary to revert drug resistance in vitro.
More recently, cyclosporin-A and analogs like PSC, which is devoid of cardiac, renal and immunosuppressive properties, have been developed and are under clinical investigation. Drugs used in clinical trials to revert P-glycoprotein-mediated MDR and examples of each. A large number of phase I and dose-finding studies have been performed with drug resistance reversal agents and cytotoxic drugs; however, randomized trials are few.
Despite occasional responses in patients with hematological malignancies, and a small positive randomized study of verapamil added to chemotherapy in untreated non-small cell lung cancer [ 21 ], three large randomized trials failed to show any benefit of reverters in influencing response to chemotherapy or survival in refractory patients with multiple myeloma [ 22 ], untreated small cell lung cancer [ 23 ] and breast cancer [ 24 ].
Other substances that appear to more efficiently block the drug efflux due to overexpression of MRP rather than of MDR -1 are being investigated [ 25 ]. Another approach for reversing or preventing the development of drug resistance to anticancer agents is the use of very high doses of chemotherapy.
Many anticancer agents, in fact, possess a steep dose-response relationship, and higher doses of a drug have a much higher therapeutic activity in several tumor types. The recent introduction of colony-stimulating factors and peripheral stem cell infusions into routine use has replaced, at least in solid tumors, the use of bone marrow transplantation, which is complicated by much higher morbidity and mortality rates. These improvements have made the administration of high-dose chemotherapy more feasible by substantially reducing the intensity and length of myelosuppression.
Randomized studies comparing traditional chemotherapy doses with high-dose chemotherapy are ongoing in several tumor types. Another way of allowing higher doses of chemotherapy to be administered is to transfect peripheral stem cells with the MDR -1 gene in order to make them more resistant to chemotherapy. Clinical studies employing this approach are also in progress.
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User Name Password Sign In. Giaccone, M. Telephone: ; Fax: Accepted January 4, Previous Section Next Section. View this table: In this window In a new window. Table 1. General mechanisms leading to cellular drug resistance. Figure 1. Table 2. Previous Section.
Mathematic modelling of drug resistance. Mechanisms of Drug Resistance in Neoplastic Cells. Google Scholar. Gottesman MM, Pastan I. The multidrug transporter, a double-edged sword. J Biol Chem ; : — Multidrug resistance gene P-glycoprotein expression in the human fetus. Am J Pathol ; : — Medline Google Scholar. Multidrug resistance from the clinical point of view. Eur J Cancer ; 27 : — Ling V.cammakakoding.cf/about-a-prince-who-counted-the.php
Cancer multidrug resistance
Does P-glycoprotein predict response to chemotherapy? J Natl Cancer Inst ; 81 : 84 — Relationship of the expression of the multidrug resistance gene product P-glycoprotein in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. Cancer Res ; 51 : — Pinedo HM, Giaccone G. P-glycoprotein: a marker of cancer cell behavior. New Engl J Med ; : — CrossRef Medline Google Scholar. Overexpression of a transporter gene in a multidrug-resistant lung cancer cell line.
Science Washington DC ; : — The relative resistance associated with BCSCs appears to be multifactorial ranging from decreased level of oxidants production and increased DNA repair efficiency that help maintain their stemness. Moreover, the preferential targeting of rapidly dividing cells by most chemotherapy enables the BCSCs in their quiescent non-cycling state to persist after therapy [ 64 , 65 ].
Another molecular mechanism mediating breast cancer resistance to trastuzumab chemotherapy is inactivation of the tumour suppressor PTEN, which activate the downstream Akt molecule and bypass HER2 activation [ 62 ]. Photodynamic therapy is an approved treatment regime for several cancer types that involves systemic use of a non-toxic light sensitive compound PS and a subsequent light excitation of the PS by an appropriate wavelength to induce cancer death [ 66 ]. This treatment modality requires three components; PS, light and molecular oxygen to exert a cytotoxic effect. The PS absorbs energy from light in the form of photon and undergo energy transfer to either tissue substrate Type I reaction or molecular oxygen Type II reaction which results in the production of superoxide anion radicals and reactive singlet oxygen molecules respectively Fig.
The photosensitization process of PDT. The triplet PS reacts with either tissue substrate Type I mechanism to form a superoxide anion radicals or with molecular oxygen to form a reactive oxygen species Type II mechanism. The consequence of excess ROS production will cause vital tissue peroxidation and initiation of cell death mechanisms [ 69 , 70 ]. The photo-damaging effect of PDT greatly depends on factors like type of PS used, dose administered, light exposure, light fluency, oxygen availability, sensitizer localization, drug administration time interval and many more [ 71 ].
It has been observed that following PDT, there are blood vessel occlusion, collapse and ultimate vascular shutdown due to excessive radical formation and hypoxia. This causes apoptosis and necrosis [ 72 ]. Moreover, PDT can also mediate destruction of tumour-infected cells through immune modulation. The radical formation results in cell signal transduction that activate apoptotic proteins and cytokine gene expression [ 73 ]. A major challenge in PDT technology is to acquire the therapeutic relevant PS level and retention in the target tissue. This is because of the presence of overexpressed multidrug resistance proteins among tumour cells which pumps out PS and prevents its localization.
This upregulation of multidrug resistance protein especially P -gp have been described as the most important resistance mechanisms. The cytoprotective functions of some intracellular antioxidants like the glutathione system, catalase, lipoamide de-hydrogenase, and superoxide dismutase which detoxify PDT-induced ROS, result in treatment resistance [ 69 ]. A major cause of cancer development is the escape of T-cell recognition thus, PDT have shown to induce T-cell mediated anti-tumour immunity [ 75 ].
Reports have shown PDT to be specific treatment modalities with fewer side effects. Emerging evidence now suggests that the damage and unique mechanism of photodynamic treatment on tumour and its microenvironment could possibly inhibit drug resistance pathways and re-sensitize resistant cells to standard therapies.
Photoactive compound used in PDT localize at cellular organelle such as the mitochondria, lysosome, endoplasmic reticulum and possibly Golgi apparatus within the cytoplasm [ 76 ]. Upon photo-damage, these intracellular membranes including their protein components are destroyed thus leading to cell death via any of the normal modes—necrosis, autophagy or apoptosis. PS that localized in the lysosome leads to spillage of proteases upon irradiation which activates the proapoptotic factor BID tBID that enhance cell death. This causes BAX translocation to the outer mitochondria membrane and stimulates the release of cytochrome c that drives the cells alone the irreversible path to apoptosis Fig.
Researchers Turn Off Multi-Drug Resistance Capabilities in Cancer Cells | Front Line Genomics
Overview of unique mechanisms of PDT-induced apoptosis on multidrug resistant cells. Light activation directly damages drug efflux pumps P -gp and BCRP involved in classical drug resistance and release PS into the cytosol which localizes on mitochondria and lysosome. Upon activation, damages the antiapoptotic BCL-2 family proteins and lysosomal membrane. The pore opening caused the release of cytochrome c and SMAC second mitochondrion-derived activator of caspases from the intermembrane mitochondrion space.
The SMAC promotes caspase activation by binding with IAPs inhibitor of apoptosis protein and cytochrome c forms complex which leads to cell death through caspase action. Membrane damage after PDT leads to depolarization, reduction of active transport and lipid peroxidation which help in activation of death signal and thus cell death. This mechanism of apoptotic induction bypasses many regulatory checkpoints that accounts for resistance and triggers increased susceptibility of tumour cells to death rather than MDR development. Some investigations have shown that photo-destruction of breast cancer resistant protein rich extracellular vesicles could facilitate photoactive drugs towards reaching its target without been entrapped or sequestrated outside the cell [ 34 ].
This approach results in direct damage to proteins involved in drug resistance and shut down tumour microvasculature, thus stimulates drug delivery and antitumor immunity [ 34 , 77 ]. The time interval between PS administration and photo-irradiation which is very unique to PDT can be utilized and exploited depending on the pharmacokinetics of the PS to shut down tumour microvasculature [ 7 ]. Photochemical internalization PCI is another novel technological approach used to facilitate the cytosolic delivery of macromolecular drugs. This drug and gene therapy delivery method is developed to release macromolecules into the cytosol and by so doing, bypass the efflux pumps proteins that transport xenobiotics out of the cancer cells.
The PCI treatment is based on same principles of PDT except in its aim which is to induce cancer cell death by the macromolecular drug delivered and not primarily by photochemical reaction [ 78 ]. PCI has been demonstrated to facilitate the intracellular release of anticancer agents or PS that are targeted for intracellular organelles.
Emerging evidence support the therapeutic potential of PCI to circumvent mechanisms associated with resistance towards chemotherapeutics [ 78 ]. Furthermore, none of the PCI components including a macromolecular drug, amphiphilic PS and light are subjected to cellular efflux which enables PCI a treatment strategy for cancer stem-like cells [ 79 ]. Additionally, several researchers have reported in vitro experimental evidence of PDT potentiation in overcoming MDR and re-sensitizing the susceptibility of tumour cells to treatment.
One of such studies includes early investigations by Kusuzaki and colleagues [ 80 ] that studied the effect of PDT using acridine orange on mouse osteosarcoma cells with MDR phenotype and observed a strong cytotoxic effect [ 80 ]. Similarly, Kulbacka et al. Feuerstein and co-workers tested the effect of a novel ALA-derived prodrug on MCF-7 resistant sublines and the result showed a higher potent effect on the viability of the resistant cells even without laser irradiation.
This indicate that ALA-derived prodrug based PDT has the effectiveness of treating resistant cancer malignancies [ 84 ]. Another most recent report by Chen et al. More also, Kukcinaviciute et al. In recent years, application of Nano-carriers and targeting technology to overcome MDR has been recognized as an important and promising field of research. This involve the use of drug delivery system loaded with PS to bypass the efflux transporters and enhance intracellular accumulation [ 87 ].
The use of Nano-carriers, such as polymeric nanoparticles, and magnetic nanoparticles can facilitate delivery of PS without been entrapped by efflux transporters [ 88 ]. A novel nanoceria-mediated drug delivery nanocomposites, synthesized by Hong and colleagues was used to load PS for targeted PDT. They reported that the nanocomposites carrying the PS selectively accumulated in lysosome triggered production of reactive oxygen species and reduced P -gp expression.
This approach promotes the effectiveness of PDT in the treatment of drug-resistant human breast cancer cells [ 88 ]. Drug delivery system combined with targeting technology holds great potential and may provide the possibilities of targeting at gene level, the proteins responsible for MDR [ 45 , 78 , 89 ]. Novel strategies to modulate MDR in cancer cells including targeting ABC transporters using substrates and inhibitors are currently underway to eliminate and suppress drug resistance [ 45 ].
For instance, Bao and colleagues were able to modulate multidrug resistance in human breast cancer using miR Their study observed that overexpression of miR down-regulated P -gp expression, and increases nuclear accumulation of doxorubicin and cytotoxicity in resistant breast cancer cells [ 38 ]. MDR transporters especially P -gp have proven to interact with various structurally unrelated compounds classified as substrates and modulators.
This substrate actively binds to and is transported in and out of the cell while modulators bind and block the transport function of the MDR transporter. The anti-MDR strategy of using an inhibitor to alter the function of the transporter proteins have shown significant clinical applications in cancer chemotherapy [ 90 ].
There are three different generations of inhibitors developed for MDR transporter up till date; first generation inhibitors including verapamil and cyclosporine A were found to reverse drug resistance profile in leukemic and lungs cancer cells respectively [ 91 , 92 ]. Its low therapeutic response and unacceptable toxicity drive the development of the second generation of inhibitors such as dexverapamil, valspodar and biricodar citrate which showed a better tolerability but displayed unwanted pharmacokinetic interaction with cytochrome P [ 45 , 93 ].
Continuous problems with MDR necessitates the development of a specific and more potent three generation MDR transporter inhibitor that can reverse MDR with almost no pharmacokinetic interaction with other chemotherapeutic drugs. This inhibitors include; tariquidar XR , zosuquidar LY , laniquidar R and elacridar F [ 45 , 93 , 94 ]. Recent studies have noted that tariquidar can also act as a substrate depending on its in vivo dosage to P -gp [ 95 ]. Another achievable approach to circumvent drug resistance besides the use of ABC transporter inhibition, is by substituting drugs that are not subject to efflux transport system.
Kathawala and his colleagues [ 44 ] in their report postulated that ABC transporter inhibitor known as chemosensitizers may be used in combination with standard chemotherapy to enhance therapeutic efficacy. Developing therapeutic strategies for breast cancer, especially the type characterized by lack of ER, PR, and HER2 expression, have been a challenge since these receptors are involved in targeted therapy. TNBC exhibit a higher risk for drug resistance and cancer relapse. In recent years, the therapeutic effects of PDT in cancer treatment are encouraging especially in palliative end point.
This remains an area of interest with the possibility of serving as an alternative to broad spectrum antibiotic-based therapy and thus limits the development of drug resistance. The treatment modality of PDT is still questioned by some scientists mostly its efficacy in huge and metastases widespread tumour. Since PS that accumulates in malignant tissue are crucial to photo-medicine, it is essential that more research should focus on the development of a suitable PS composed of either antibody or nanoparticles to enhance efficiency and reduce the chances of drug efflux pumps.
This will further compensate the lack of specificity and selectivity potential of a raw PS. Recent advancements have shown combination treatment strategies comprising PDT and other concurrent treatments to have a better response in cancer recurrence. The improved response was due to molecular response, boosted antitumor immunity and susceptibility of cancer cells following PDT which leads to improve overall treatment outcome.
Immunotherapy using drug delivery system could also be used to bypass the efflux transporters and deliver PS into tumour cells thus maximize treatment efficacy and thwart survival mechanism in resistant tumour. In addition to this development, PDT resistant cells should also be used as a model to further study the impact of PDT on the cellular targets. Moreover, PDT studies on MDR tumour cells with focus on the multidrug resistant phenotype on PS uptake might shed light and contribute to the circumvention of drug resistance.
It is expected that this review will hopefully stimulate innovative preclinical and clinical PDT research against multidrug resistance cancer cells. Patel S. Breast cancer: lesser-known facets and hypotheses. Biomed Pharmacother. American Cancer Society. Tobias J, Hochhanser D. Breast cancer in cancer and its management. New York: Wiley; Biological subtypes of breast cancer: current concepts and implications for recurrence patterns. Multidrug resistance characterization in multicellular tumour spheroids from two human lung cancer cell lines.
Cancer Cell Int. Mammalian drug efflux transporters of the ATP binding cassette ABC family in multidrug resistance: a review of the past decade. Cancer Lett. The role of photodynamic therapy in overcoming cancer drug resistance. Photochem Photobiol Sci. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res. Deconstructing breast cancer cell biology and the mechanisms of multidrug resistance. Biochim Biophys Acta. Genetic alterations in hereditary breast cancer. Ann Oncol. Super-enhancers in the control of cell identity and disease. Master transcription factors and mediator establish super-enhancers at key cell identity genes.
Tripathy D, Benz CC. Activated oncogenes and putative tumour suppressor genes involved in human breast cancers. Oncogenes and tumor suppressor genes in human malignancies. Cancer treatment and research. Boston: Springer; Estrogen receptor variants. J Mammary Gland Biol Neoplasia. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Effects of the lifestyle habits in breast cancer transcriptional regulation. Emerging patterns of somatic mutations in cancer. Nat Rev Genet.
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J Extracell Vesicles.
Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches.
The mutations or hypermethylation in the promoter of following genes cause cancer. For example, the mutation or hypermethylation of hMLH1 gene can cause the colorectal cancer. Similarly, the demethylation of hMLH1 promoter gene by DAC and recovery of the mismatch repair system causes the colorectal cancer cells to become sensitive to 5-FU fluorouracil MicroRNAs are much too short to code for protein and instead play important roles in regulating gene expression.
They regulate most protein-coding genes, including important genes in cancer and especially in cancer drug resistance generation. There are three mechanisms involved in gene silencing with miRNA process: 1. Cleavage of the mRNA strand into two pieces, 2. Destabilization of the mRNA through shortening of its poly A tail and, 3. Less efficient translation of the mRNA into proteins by ribosomes.
Recent studies in miRNA profiling confirmed that these small molecules play an important role in the development of chemosensitivity or chemoresistance in different types of cancer Table 2. Also, these small molecules could serve as a biomarker for prognosis and survival in response to chemotherapy. We know that the overdose of the antibiotics leads to drug resistance to the bacteria. Thus, the rapid cell division and high frequencies of mutations cause the natural selection of the resistant strains of these bacteria and survive in the presence of the certain drugs.
Also, the human cancer cells with high proliferation rate are genetically unstable, so, the drug resistance could occur in a similar way. Interestingly, the studies approved that cancer cells which are smart, and resistance to the cellular stresses and agents have been created via altered mechanisms of the cell biology. The cancer drug resistance is a complex phenomenon.
Thus; the combination therapy is the best option for drug resisted type of cancers. In this context, we reviewed different involved mechanisms in drug resistance and finally, we found the epigenetic drugs and synergy or an additive effect between established chemotherapeutic agents in combination with each other might provide a new strategy in drug resistance cancers. New studies suggested that cancer cells could sensitize to chemotherapeutic agents, via RNAi technique such as miRNA , consequently with RNAi strategy espcially siRNA the chemotherapy drug resistance genes suppressed and limited the drug resistance in the resisted tumoral cells.
The replacement of tumor suppressor miRNA and suppression of oncomiRs can regulate cancerous cells by suppressing their target genes which are involved in cancer development especially cancer drug resistance.
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National Center for Biotechnology Information , U. Journal List Adv Pharm Bull v. Adv Pharm Bull. Published online Sep Find articles by Behzad Mansoori. Find articles by Ali Mohammadi. Find articles by Sadaf Davudian. Find articles by Solmaz Shirjang. Find articles by Behzad Baradaran. Author information Article notes Copyright and License information Disclaimer. This is an Open Access article distributed under the terms of the Creative Commons Attribution CC BY , which permits unrestricted use, distribution, and reproduction in any medium, as long as the original authors and source are cited.
No permission is required from the authors or the publishers. This article has been cited by other articles in PMC. Abstract Anticancer drugs resistance is a complex process that arises from altering in the drug targets. Introduction By providing advances in the cancer research, our knowledge of the cancer biological characteristics is updating every day. Open in a separate window. Figure 1. Intrinsic and extrinsic factors in drug resistance Tumor heterogeneity Intra-tumor heterogeneity can be observed at many different cancer levels and may be assignable to a number of different factors that primarily occur at the cellular level.
Tumor microenvironment Growing evidence supports the important role of tumor microenvironment in drug resistance discussion as the main reason for the relapse and incurability of various cancers. Cancer stem cells Cancer stem-cell populations have been detected in a variety of hematopoietic and solid tumors, and might be the cell of origin of hematopoietic and solid tumors. Inactivation of the anticancer drugs The anticancer drugs efficiency and their activity are dependent on the complex mechanisms. Multi-drug resistance MDR Multi-drug resistance MDR in the cancer chemotherapy has been pointed out as the ability of cancer cells to survive against a wide range of anti-cancer drugs Figure 2.
Reducing the absorption of the drugs The absorption of the anticancer agent into the tumoral cells can occur by passive transfer e. Inhibition of the cell death apoptosis pathway blocking The cell death is mediated by the three important events such as necrosis, apoptosis, and autophagy. Changing the drug metabolism Chemotherapeutic agent metabolisms can be occurred by enzymes. Changing the chemotherapeutic agents targets The effect of chemotherapeutic agents could have been depended on the modifications such as the mutations and changes in the expression levels of their targets.
Table 1 Disease and drug resistance mechanisms and pathways interruption. Epigenetic altering caused drug resistance One of the important mechanisms of the drug resistance in the cancer therapy is the epigenetic altering. Table 2 miRNAs involved in cancer drug resistance. Conclusion We know that the overdose of the antibiotics leads to drug resistance to the bacteria.
Ethical Issues Not applicable. Conflict of Interest The authors declare no conflict of interests. References 1. Clinical implications of the cancer genome. J Clin Oncol. Goldenberg MM. Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. Clin Ther. Molecular mechanisms of drug resistance.
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Stem cell altruism may serve as a novel drug resistance mechanism in oral cancer. Cancer Res. Settleman J. Cancer: Bet on drug resistance. Tumour stem cells and drug resistance. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the philadelphia chromosome. N Engl J Med.
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