Mechanisms Of Multidrug Resistance Research Articles

Monoterpene indole alkaloids as leads for targeting multidrug resistant cancer cells from the African medicinal plant Tabernaemontana elegans

Multidrug resistance (MDR) is the main challenge in cancer treatment. Several mechanisms of MDR have been proposed, such as an increased drug efflux due to the overexpression of ABC drug transporter proteins, or a deregulation of apoptosis. Thus, the development of ABC-transporter modulators and the search for effective apoptosis inducers have been considered realistic strategies for overcoming MDR. Exploiting collateral sensitivity is also comprised among the most promising approaches to tackle MDR. Aiming at obtaining a library of monoterpene indole alkaloids for overcoming MDR, we have been carrying out the phytochemical study of the African medicinal plant Tabernaemontana elegans (Apocynaceae), by using both approaches isolation and molecular derivatization. The results, summarized in this review, showed that several indole alkaloids, of both natural origin or obtained by derivatization, are promising potential lead structures for reversing MDR.

CKT0353, a novel microtubule targeting agent, overcomes paclitaxel induced resistance in cancer cells.

Microtubule targeting agents (MTAs) are extensively used in cancer treatment and many have achieved substantial clinical success. In recent years, targeting microtubules to inhibit cell division has become a widespread pharmaceutical approach for treatment of various cancer types. Nevertheless, the development of multidrug resistance (MDR) in cancer remains a major obstacle for successful application of these agents. Herein, we provided the evidence that CKT0353, α-branched α,β-unsaturated ketone, possesses the capacity to successfully evade the MDR phenotype as an MTA. CKT0353 induced G2/M phase arrest, delayed cell division via spindle assembly checkpoint activation, disrupted the mitotic spindle formation and depolymerized microtubules in human breast, cervix, and colorectal carcinoma cells. Molecular docking analysis revealed that CKT0353 binds at the nocodazole binding domain of β-tubulin. Furthermore, CKT0353 triggered apoptosis via caspase-dependent mechanism. In addition, P-glycoprotein overexpressing colorectal carcinoma cells showed higher sensitivity to this agent when compared to their sensitive counterpart, demonstrating the ability of CKT0353 to overcome this classic MDR mechanism involved in resistance to various MTAs. Taken together, these findings suggest that CKT0353 is an excellent candidate for further optimization as a therapeutic agent against tumors with MDR phenotype.

P098 Molecular mechanisms of multidrug resistance in Pseudomonas aeruginosa cystic fibrosis strains isolated during 10 years of persistence

P098 Molecular mechanisms of multidrug resistance in Pseudomonas aeruginosa cystic fibrosis strains isolated during 10 years of persistence

Current Applications of Nanoemulsions in Cancer Therapeutics.

Nanoemulsions are pharmaceutical formulations composed of particles within a nanometer range. They possess the capacity to encapsulate drugs that are poorly water soluble due to their hydrophobic core nature. Additionally, they are also composed of safe gradient excipients, which makes them a stable and safe option to deliver drugs. Cancer therapy has been an issue for several decades. Drugs developed to treat this disease are not always successful or end up failing, mainly due to low solubility, multidrug resistance (MDR), and unspecific toxicity. Nanoemulsions might be the solution to achieve efficient and safe tumor treatment. These formulations not only solve water-solubility problems but also provide specific targeting to cancer cells and might even be designed to overcome MDR. Nanoemulsions can be modified using ligands of different natures to target components present in tumor cells surface or to escape MDR mechanisms. Multifunctional nanoemulsions are being studied by a wide variety of researchers in different research areas mainly for the treatment of different types of cancer. All of these studies demonstrate that nanoemulsions are efficiently taken by the tumoral cells, reduce tumor growth, eliminate toxicity to healthy cells, and decrease migration of cancer cells to other organs.

The role of intercellular transfer of P-glycoprotein in tumor drug resistance

Multidrug resistance is a major cause of clinical failure of tumor chemotherapy, study on the mechanisms of tumor multidrug resistance has been becoming a fascinating area in the field of tumor chemotherapy. The tumor multidrug resistance is generally considered to be due to the gene mutation, amplification or epigenetic changes that affect the uptake, metabolism or excretion of tumor drugs. P-glycoprotein is a transmembrane glycoprotein encoded by multidrug resistance gene MDR1, which leads to the principal contributor to tumor multidrug resistance. Research suggests that P-glycoprotein can metastasize through the tumor cells, thereby affecting tumor resistance. This article reviews the role of intercellular transfer of P-glycoprotein in tumor drug resistance. Key words: P-glycoprotein; Drug resistance, neoplasm; Membranin transfer

Thermal-Responsive Carbon Monoxide (CO) Delivery Expedites Metabolic Exhaustion of Cancer Cells toward Reversal of Chemotherapy Resistance.

Multidrug resistance (MDR) is the main cause of chemotherapy failure, and the mechanism of MDR is largely associated with drug efflux mediated by the adenosine triphosphate (ATP)-binding cassette transporters. Herein, an NIR-light-triggered CO release system based on mesoporous Prussian blue nanoparticles (PB NPs) was developed to reverse MDR via CO-induced metabolic exhaustion. Pentacarbonyl iron (Fe(CO)5) as the CO producer was coupled to PB NPs via coordination interaction, and doxorubicin (Dox) was encapsulated into the pores of PB NPs. After layer-by-layer (LBL) coating, the NPs showed desired serum stability to enhance tumor accumulation. Upon tumor-site-specific NIR light (808 nm) irradiation, the nonlethal temperature elevation cleaved the Fe–CO bond to release CO. CO then expedited mitochondrial metabolic exhaustion to block ATP synthesis and inhibit ATP-dependent drug efflux, thus reversing MDR of the Dox-resistant MCF-7/ADR tumors to potentiate the anticancer efficacy of Dox. In the meantime, CO-mediated mitochondrial exhaustion could upregulate the proapoptotic protein, caspase 3, thus inducing cellular apoptosis and enabling a synergistic anticancer effect with chemotherapy. To the best of our knowledge, this is the first time MDR has been overcome using a CO delivery system. This study provides a promising strategy to realize an effective and safe treatment against MDR tumors and reveals new insights in the use of CO for cancer treatment.

Intracellular Doppler Spectroscopy detects altered drug response in SKOV3 tumor spheroids with silenced or inhibited P-glycoprotein

Intracellular Doppler spectroscopy is a form of low-coherence digital holography based upon Doppler detection of scattered light that measures drug response/resistance in tumor spheroids, xenografts, and clinical biopsies. Multidrug resistance (MDR) is one of the main causes of ineffective cancer treatment. One MDR mechanism is mediated by the MDR1 gene that encodes the drug efflux pump P-glycoprotein (Pgp). Overexpression of Pgp in some cancers is associated with poor chemotherapeutic response. This paper uses intracellular Doppler spectroscopy to detect Pgp-mediated changes to drug response in 3D tissues grown from an ovarian cancer cell line (SKOV3). The SKOV3 cell line was incrementally exposed to cisplatin to create a cell line with increased Pgp expression (SKOV3cis). Subsequently, MDR1 in a subset of these cells was silenced in SKOV3cis using shRNA to create a doxycycline inducible, Pgp-silenced cell line (SKOV3cis-sh). A specific Pgp inhibitor, zosuquidar, was used to study the effects of Pgp inhibition on the Doppler spectra. Increased drug sensitivity was observed with Pgp silencing or inhibition as determined by drug IC50s of paclitaxel-response of silenced Pgp and doxorubicin-response of inhibited Pgp, respectively. These results indicate that intracellular Doppler spectroscopy can detect changes in drug response due to silencing or inhibition of a single protein associated with drug resistance with important consequences for personalized medicine.

Systematic Review on Cytotoxic and Anticancer Potential of N-Substituted Isatins as Novel Class of Compounds Useful in Multidrug-Resistant Cancer Therapy: In Silico and In Vitro Analysis.

As the emergence of resistance to clinical cancer treatments poses a significant problem in cancer management, there is a constant need to explore novel anticancer agents which have the ability to overcome multidrug resistance (MDR) mechanisms. The search for the development of novel isatin-based antitumor agents accelerated after the approval by the Food and Drug Administration (FDA) of sunitinib malate, a C-3 isatin derivative, as a multitargeted receptor tyrosine kinase inhibitor. However, it is interesting to note that, over the last decade, various N-substituted analogs of isatin with intact carbonyl functionalities have been found to show more promising anticancer potential than its C-3 derivatives. Microtubule-targeting agents are a class of anticancer drugs which affect mitosis by targeting microtubules and suppressing their dynamic behavior. This review presents a systematic compilation of the invitro cytotoxic and anticancer properties of various N-substituted isatins and illustrates their mechanism of action to overcome MDR by acting as microtubule-destabilizing agents. Predictions of the biological activities and cytotoxic effects of potential N-substituted isatins against various cancer cell lines have also been performed using the PASS computer-aided drug discovery program. Findings from such invitro and insilico studies will act as a guide for the development of structure-activity relationship and will facilitate the design and exploration of more potent analogs of isatin with high potency and lower side effects for treatment of drug-resistant cancer. Mechanism of action of N-substituted isatin as microtubule-destabilizing agent on tumor cells. N-Substituted isatins bind to colchicine binding site on β-tubulin, which inhibits microtubule polymerization and thereby destabilizes microtubule dynamics, resulting in mitotic arrest leading to tumor cell growth suppression.

Clinical and Prognostic Significance of Cell Sensitivity to Chemotherapy Detected in vitro on Treatment Response and Survival of Leukemia Patients.

Multidrug resistance (MDR) is a major challenge in leukemia treatment. The objective of this study was to identity predictors of MDR to allow for rapid and economical assessment of the efficacy of planned antitumor therapy for leukemia patients. The study included 113 patients with acute and chronic leukemias. Prior to antitumor therapy, we measured the sensitivity of tumor cells of patients to the panel of chemotherapeutic drugs, together with MDR1 mRNA and P-glycoprotein (P-gp) expression as one of the mechanisms of MDR, and compared these data with the response to therapy. The scales for leukemia patients according to therapy response, drug sensitivity of tumor cells, MDR1 mRNA and P-gp levels, and the presence of unfavorable immunological and cytogenetic markers were introduced for subsequent correlation analysis. We show that the drug resistance of tumor cells of leukemia patients estimated in vitro at diagnosis correlates with a poor response to chemotherapy and is usually combined with aberrant and immature immunological markers, cytogenetic abnormalities, and a high expression of MDR1 mRNA and P-gp. All together, these factors indicate unfavorable prognosis and low survival of leukemia patients. Thus, the sensitivity of tumor cells to chemotherapeutic drugs measured in vitro at diagnosis may have prognostic value for individual types of leukemia.

Glesatinib, a c-MET/SMO Dual Inhibitor, Antagonizes P-glycoprotein Mediated Multidrug Resistance in Cancer Cells.

Multidrug resistance (MDR) is one of the leading causes of treatment failure in cancer chemotherapy. One major mechanism of MDR is the overexpressing of ABC transporters, whose inhibitors hold promising potential in antagonizing MDR. Glesatinib is a dual inhibitor of c-Met and SMO that is under phase II clinical trial for non-small cell lung cancer. In this work, we report the reversal effects of glesatinib to P-glycoprotein (P-gp) mediated MDR. Glesatinib can sensitize paclitaxel, doxorubicin, colchicine resistance to P-gp overexpressing KB-C2, SW620/Ad300, and P-gp transfected Hek293/ABCB1 cells, while has no effect to their corresponding parental cells and negative control drug cisplatin. Glesatinib suppressed the efflux function of P-gp to [3H]-paclitaxel and it didn't impact both the expression and cellular localization of P-gp based on Western blot and immunofluorescent analysis. Furthermore, glesatinib can stimulate ATPase in a dose-dependent manner. The docking study indicated that glesatinib interacted with human P-gp through several hydrogen bonds. Taken together, c-Met/SMO inhibitor glesatinib can antagonize P-gp mediated MDR by inhibiting its cell membrane transporting functions, suggesting new application in clinical trials.

Targeting siRNA in colorectal cancer therapy: Nanotechnology comes into view.

Colorectal cancer (CRC) is known as one of the most important causes of death and mortality worldwide. Although several efforts have been made for finding new therapies, no achievements have been made in this area. Multidrug resistance (MDR) mechanisms are one of the key factors that could lead to the failure of chemotherapy. Moreover, it has been shown that various chemotherapy drugs are associated with several side effects. Hence, it seems that finding new drugs or new therapeutic platforms is required. Among different therapeutic approaches, utilization of nanoparticles (NPs) for targeting a variety of molecules such as siRNAs are associated with good results for the treatment of CRC. Targeting siRNA-mediated NPs could turn off the effects of oncogenes and MDR-related genes. In the current study, we summarized various siRNAs targeted by NPs which could be used for the treatment of CRC. Moreover, we highlighted other routes such as liposome for targeting siRNAs in CRC therapy.

Application of Solid Lipid Nanoparticles to Improve the Efficiency of Anticancer Drugs.

Drug delivery systems have opened new avenues to improve the therapeutic effects of already-efficient molecules. Particularly, Solid Lipid Nanoparticles (SLNs) have emerged as promising nanocarriers in cancer therapy. SLNs offer remarkable advantages such as low toxicity, high bioavailability of drugs, versatility of incorporation of hydrophilic and lipophilic drugs, and feasibility of large-scale production. Their molecular structure is crucial to obtain high quality SLN preparations and it is determined by the relationship between the composition and preparation method. Additionally, SLNs allow overcoming several physiological barriers that hinder drug delivery to tumors and are also able to escape multidrug resistance mechanisms, characteristic of cancer cells. Focusing on cell delivery, SLNs can improve drug delivery to target cells by different mechanisms, such as passive mechanisms that take advantage of the tumor microenvironment, active mechanisms by surface modification of SLNs, and codelivery mechanisms. SLNs can incorporate many different drugs and have proven to be effective in different types of tumors (i.e., breast, lung, colon, liver, and brain), corroborating their potential. Finally, it has to be taken into account that there are still some challenges to face in the application of SLNs in anticancer treatments but their possibilities seem to be high.

ABCB1 and BMI1 mRNA expression in patients with chronic myeloid leukemia: impact on imatinib efficacy.

BackgroundATP-binding cassette transporters are important in the mechanism of multidrug resistance. ABCB1 displays a high affinity for imatinib. BMI1 is a polycomb group protein thought to be overexpressed in leukemic cells.MethodsThis study was conducted to investigate the prognostic value of ABCB1 and BMI1 expressions in chronic myeloid leukemia (CML). Expression levels were measured in 81 patients newly diagnosed with CML and 20 healthy controls by real time reverse transcription- PCR.ResultsThe ABCB1 expression levels did not differ between patients with CML and controls. Low ABCB1 mRNA levels were observed in patients who achieved an optimal response compared to suboptimal and resistant cases (P=0.005). Non-responders showed the highest ABCB1 levels. ABCB1 expression did not affect the progression-free survival (PFS) of patients. BMI1 expression was higher in patients than that in controls (P=0.001). Patients in advanced phases expressed higher levels of BMI1 than those in the chronic phase (P=0.004). High BMI1 expression was associated with a shorter PFS.ConclusionABCB1 mRNA expression may serve as a predictor of the optimal response to imatinib treatment in patients with CML. BMI1 expression was higher in the accelerated and blastic crisis phases of CML and associated with a shorter PFS.

The antibiotic resistance and pathogenicity of a multidrug-resistant Elizabethkingia anophelis isolate.

Elizabethkingia anophelis 12012‐2 PRCM was isolated from a patient with multiple organ dysfunction syndrome and lower respiratory tract infection in China. Minimum inhibitory concentration (MIC) analysis demonstrated that it was resistant to 20 antibiotics including trimethoprim/sulfamethoxazole and ciprofloxacin, which were effective for the elimination of other Elizabethkingia infections. To investigate multidrug resistance and pathogenicity mechanisms, we analyzed genome features of 12012‐2 PRCM and compared them to the other Elizabethkingia species. The draft genome size was 4.02 Mb with a GC content of 32%, comparable to that of other E. anophelis strains. Phylogenetic analysis showed that E. anophelis 12012‐2 PRCM formed a sister group with E. anophelis 502, distinct from clades formed by other clinical and environmental E. anophelis isolates. E. anophelis 12012‐2 PRCM contained multiple copies of β‐lactamase genes as well as genes predicted to function in antimicrobial efflux. It also contained 92 genes that were potentially involved in virulence, disease, and defense, and were associated with resistance and pathogenicity. Comparative genomic analysis showed high homology among three clinical and two environmental E. anophelis strains having a variety of similar antibiotic resistance and virulence factor genes, and similar genomic structure. Applications of this analysis will contribute to understanding the antibiotic resistance and pathogenic mechanisms of E. anophelis infections, which will assist in the management of infections as it increases in prevalence.

Vielanin P enhances the cytotoxicity of doxorubicin via the inhibition of PI3K/Nrf2-stimulated MRP1 expression in MCF-7 and K562 DOX-resistant cell lines

BackgroundCancer cells that are resistant to structurally and mechanically unrelated anticancer drugs are said to have multidrug resistance (MDR). The overexpression of the ATP-binding cassette (ABC) transporter is one of the most important mechanisms of MDR. Vielanin P (VP), a dimeric guaiane from the leaves of Xylopia vielana, has the potential to reverse multidrug resistance. PurposeTo evaluate the meroterpenoid compound VP as a low cytotoxicity MDR regulator and the related mechanisms. MethodsCell viability was determined by CCK-8 and MTT assays. Apoptosis and the accumulation of doxorubicin (DOX) and 5(6)-carboxyfluorescein diacetate (CFDA) were determined by flow cytometry. We determined mRNA levels by quantitative real-time polymerase chain reaction (qRT-PCR). Protein levels were analyzed by Western blotting and immunofluorescence. ResultsIn the MCF-7 and K562 DOX-resistant cell lines, VP treatment (10 μM or 20 μM) enhanced the activity of chemotherapeutic agents. We found that VP selectively inhibited MRP1 mRNA but not MDR1 mRNA. VP enhanced DOX-induced apoptosis and reduced colony formation in the presence of DOX in drug-resistant cells. Moreover, VP increased the accumulation of DOX and the MRP1-specific substrate CFDA. In addition, VP reversed MRP1 protein levels and the accumulation of DOX and CFDA in MRP1-overexpressing MCF-7 and K562 cells. Thus, the mechanism of MDR reversal by VP is MRP1-dependent. Furthermore, we found that the inhibitory effect of VP on MRP1 is PI3K/Nrf2-dependent. ConclusionThese results support the potential therapeutic value of VP as an MDR-reversal agent by inhibiting MRP1 via PI3K/Nrf2 signaling.

Antiseptic chlorhexidine in activated sludge: Biosorption, antimicrobial susceptibility, and alteration of community structure

Chlorhexidine (CHX) is a broad-spectrum antimicrobial, which may pose environmental health risks. This study examined the removal potential and the mechanisms regulating the fate of CHX in activated sludge (AS). Bioreactors inoculated with AS removed 74 ± 8% and 81 ± 6% of CHX at steady state while receiving 0.5 and 1 mg/L CHX, respectively. Analysis of the removal pathways showed that biosorption, rather than biological breakdown or other abiotic losses, largely (>70%) regulated the removal of CHX. 16S rRNA gene-based analysis revealed that CHX selected for Luteolibacter (4.3–10.1-fold change) and Runella (6.2–14.1-fold change) with potential multi-drug resistance mechanisms (e.g., efflux pumps). In contrast, it significantly reduced core members (Comamonadaceae and Flavobacteriaceae) of AS, playing a key role in contaminant removal and floc formation directly associated with the performance of WWTPs (e.g., wastewater effluent quality). Antimicrobial susceptibility testing showed that 0.4–1.3 mg/L of CHX can be sublethal to AS. Our work provided new insights into the fate of CHX in urban waste streams and the potential toxicity and effects on the structure and function of AS, which has practical implications for the management of biological WWTPs treating CHX.

Cisplatin-loaded PLGA nanoparticles for HER2 targeted ovarian cancer therapy.

The conventional treatment (cytoreduction combined with cisplatin/carboplatin and taxane drugs) of ovarian cancer has a high rate of failure and recurrence despite a favorable initial response. This lack of success is usually attributed to the development of multidrug resistance mechanisms by cancer cells and avoidance of the anti-growth effects of monoclonal targeted therapeutic antibodies. The disease, like other cancers, is characterized by the overexpression of molecular markers, including HER2 receptors. Preclinical and clinical studies with trastuzumab, a HER2-targeted therapeutic antibody, reveal a low improvement of the outcomes of HER2 positive ovarian cancer patients. Therefore, here, we propose a cisplatin-loaded, HER2 targeted poly(lactic-co-glycolic) nanoplatform, a system capable to escape the drug-efflux effect and to take advantage of the overexpressed HER2 receptors, using them as docks for targeted chemotherapy. The NP/trastuzumab ratio was determined after fluorescein labeling of antibodies and quantification of fluorescence in NPs. The system was also characterized in terms of size, zeta potential, drug release kinetics, cytotoxicity and cellular internalization in the epithelial ovarian cancer cell line SKOV-3, and compared with the HER2 negative breast cancer cell line HCC70. Our results show an increased cytotoxicity of NPs as compared to free cisplatin, and moreover, an enhanced internalization and cytotoxicity due to the bionfunctionalization of NPs with the monoclonal antibody.

The oral α and β tubulin inhibitor, VERU-111, for the treatment of metastatic castration-resistant and androgen blocking agent-resistant prostate cancer in nonclinical toxicity studies.

299 Background: A dose limiting toxicity of taxane chemotherapy, including docetaxel and cabazitaxel, is neutropenia. VERU-111 is a novel, oral aand btubulin inhibitor that blocks tubulin polymerization and is not a substrate for multi-drug resistance mechanisms. Nonclinical toxicity studies were recently performed in order to assess the effects of daily, high-dose administration of orally dosed daily VERU-111. Methods: Toxicity of VERU-111 was evaluated in a 28-day oral dosing toxicity study which was conducted in both rats and dogs. These studies were performed at an independent facility under GLP conditions. Results: In both species evaluated, at oral doses of ≤3 mg/kg/day (rat) and ≤8 mg/kg/day (dog) there were no significant observed findings of neutropenia, myelosuppression, or abnormal liver function. Conclusions: In contrast to cabazitaxel and docetaxel, which are given once every 3 weeks IV, VERU-111 given oral, daily for 28 days in toxicity studies in dog and rat did not result in neutropenia, and myelosuppression. Furthermore, VERU-111 orally each day did not affect liver function tests. These nonclinical toxicity studies provide the basis for progressing VERU-111 into a Phase 1b/2 study which targets men with metastatic castration and androgen blocking agent (abiraterone and enzalutamide) resistant prostate cancer.

CM082 Enhanced the Sensitivity of Chemotherapeutic Agents by Inhibiting the Function of ABCG2

Background: Overexpression of ATP-binding cassette (ABC) transporters was one of the important mechanisms of multidrug resistance (MDR). Some tyrosine kinase inhibitors (TKIs) such as CM082 might be the potential ABC-transporter inhibitors due to their similar ATP binding sites to tyrosine kinase, which could potentially reverse MDR. Methods: MTT assay and H460/MX20 cell xenograft model were established to evaluate the reversal MDR efficacy in vitro and in vivo. Drug efflux assay, intracellular drug accumulation and cellular localization assay were measured by flow cytometry. Competition of CM082 for photolabeling of ABCG2 with [125I]- IAAP was performed to ascertain the binding sites. Vanadate-sensitive ATPase activity of ABCG2 was measured to evaluate the effect of CM082 on ATP hydrolysis. Western blotting and RT-PCR were employed to study the effect of CM082 on protein and mRNA expression levels. Findings: CM082 could enhance the efficacy of chemotherapeutic substrate in ABCG2-overexpressing MDR cancer cells both in vitro and in vivo. CM082 significantly increased ABCG2 substrates intracellular accumulation by inhibiting the efflux of ABCG2, stimulated ABCG2 ATPase activity and competed with [125I]-IAAP photolabeling of ABCG2. CM082 did neither alter ABCG2 expression at protein and mRNA levels nor inhibit ErbB downstream signaling of AKT and ERK. Interpretation: This study indicates that CM082 could enhanced the sensitivity of chemotherapeutic agents in vitro and in vivo by inhibiting the activity of ABCG2, suggests CM082 might be potential ABC modulator to overcome MDR. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Interest: There are no conflicts of interest to disclose. Ethical Approval: The protocol obtained approval from the Institutional Animal Care and Use Committee of Sun Yat-Sen University Cancer Center.

Drug resistance‐related microRNAs in osteosarcoma: Translating basic evidence into therapeutic strategies

Although the application of multiple chemotherapy brought revolutionary changes to improve overall survival of osteosarcoma patients, the existence of multidrug resistance (MDR) has become a great challenge for successful osteosarcoma treatment in recent decades. Substantial studies have revealed various underlying mechanisms of MDR in cancers. As for osteosarcoma, evidence has highlighted that microRNAs (miRNAs) can mediate in the processes of DNA damage response, apoptosis avoidance, autophagy induction, activation of cancer stem cells, and signal transduction. Besides, these drug resistance‐related miRNAs showed much promise for serving as candidates for predictive biomarkers of poor outcomes and shorter survival time, and therapeutic targets to reverse drug resistance and overcome treatment refractoriness. This review aims to demonstrate the potential molecular mechanisms of miRNAs‐regulated drug resistance in osteosarcoma, and provide insight in translating basic evidence into therapeutic strategies.