Overcoming Ovarian Cancer Drug Resistance with a Cold Responsive Nanomaterial.
Ontology highlight
ABSTRACT:
SUBMITTER: Wang H
PROVIDER: S-EPMC5968444 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Pancreatic cancer has the worst survival rate of all cancers. The current standard care for metastatic pancreatic cancer is gemcitabine, however, the success of this treatment is poor and overall survival has not improved for decades. Drug resistance (both intrinsic and acquired) is thought to be a major reason for the limited benefit of most pancreatic cancer therapies.Previous studies have indicated various mechanisms of drug resistance in pancreatic cancer, including changes in individual genes or signaling pathways, the influence of the tumor microenvironment, and the presence of highly resistant stem cells. This review summarizes recent advances in the mechanisms of drug resistance in pancreatic cancer and potential strategies to overcome this.Increasing drug delivery efficiency and decreasing drug resistance is the current aim in pancreatic cancer treatment, and will also benefit the treatment of other cancers. Understanding the molecular and cellular basis of drug resistance in pancreatic cancer will lead to the development of novel therapeutic strategies with the potential to sensitize pancreatic cancer to chemotherapy, and to increase the efficacy of current treatments in a wide variety of human cancers.
| S-EPMC3111812 | biostudies-literature
Project description:Severe multidrug resistance (MDR) often develops in the process of chemotherapy for most small molecule anticancer drugs, which results in clinical chemotherapy failures. Methods: Here, a nanodrug is constructed through the self-assembly of amphiphilic drug-inhibitor conjugates (ADIC) containing a redox-responsive linkage for reversing the multidrug resistance (MDR) in cancer treatment. Specifically, hydrophilic anticancer irinotecan (Ir) and hydrophobic P-gp protein inhibitor quinine (Qu) are linked by a redox responsive bridge for overcoming MDR of tumors. Results: Ir-ss-Qu is able to self-assemble into nanoparticles (NPs) in water and shows the longer blood retention half-life compared with that of free Ir or Qu, which facilitates drug accumulation in tumor site. After endocytosis of Ir-ss-Qu NPs by drug-resistant tumor cells, the disulfide bond in the linkage between Ir and Qu is cleaved rapidly induced by glutathione (GSH) to release anticancer drug Ir and inhibitor Qu synchronously. The released Qu can markedly reduce the expression of P-gp in drug-resistant tumor cells and inhibits P-gp to pump Ir out of the cells. The increased concentration of intracellular Ir can effectively improve the therapeutic efficacy. Conclusions: Such redox-responsive Ir-ss-Qu NPs, as a drug delivery system, exhibit very high cytotoxicity and the most effective inhibitory to the growth of drug-resistant breast cancer compared with that of free therapeutic agents in vitro and in vivo.
| S-EPMC6735370 | biostudies-literature
Project description:Platinum chemotherapy remains the cornerstone of treatment for epithelial ovarian cancer (OC) and Poly (ADP-ribose) polymerase inhibitors (PARPi) now have an established role as maintenance therapy. The mechanisms of action of these agents is, in many ways, complementary, and crucially reliant on the intracellular DNA Damage Repair (DDR) response. Here, we review mechanisms of primary and acquired resistance to treatment with platinum and PARPi, examining the interplay between both classes of agents. A key resistance mechanism appears to be the restoration of the Homologous Recombination (HR) repair pathway, through BRCA reversion mutations and epigenetic upregulation of BRCA1. Alterations in non-homologous end-joint (NHEJ) repair, replication fork protection, upregulation of cellular drug efflux pumps, reduction in PARP1 activity and alterations to the tumour microenvironment have also been described. These resistance mechanisms reveal molecular vulnerabilities, which may be targeted to re-sensitise OC to platinum or PARPi treatment. Promising therapeutic strategies include ATR inhibition, epigenetic re-sensitisation through DNMT inhibition, cell cycle checkpoint inhibition, combination with anti-angiogenic therapy, BET inhibition and G-quadruplex stabilisation. Translational studies to elucidate mechanisms of treatment resistance should be incorporated into future clinical trials, as understanding these biologic mechanisms is crucial to developing new and effective therapeutic approaches in advanced OC.
| S-EPMC7352566 | biostudies-literature
Project description:Prostate cancer (PCa) is the second most common cancer in men. Common treatments include active surveillance, surgery, or radiation. Androgen deprivation therapy and chemotherapy are usually reserved for advanced disease or biochemical recurrence, such as castration-resistant prostate cancer (CRPC), but they are not considered curative because PCa cells eventually develop drug resistance. The latter is achieved through various cellular mechanisms that ultimately circumvent the pharmaceutical's mode of action. The need for novel therapeutic approaches is necessary under these circumstances. An alternative way to treat PCa is by repurposing of existing drugs that were initially intended for other conditions. By extrapolating the effects of previously approved drugs to the intracellular processes of PCa, treatment options will expand. In addition, drug repurposing is cost-effective and efficient because it utilizes drugs that have already demonstrated safety and efficacy. This review catalogues the drugs that can be repurposed for PCa in preclinical studies as well as clinical trials.
| S-EPMC8883996 | biostudies-literature
Project description:Most of the prostate cancers (PCa) in advanced stage will progress to castration-resistant prostate cancer (CRPC). Within CRPC group, 50-70% of the patients will develop bone metastasis in axial and other regions of the skeleton. Once PCa cells spread to the bone, currently, no treatment regimens are available to eradicate the metastasis, and cancer-related death becomes inevitable. In 2012, it is estimated that there will be 28,170 PCa deaths in the United States. Thus, PCa bone metastasis-associated clinical complications and treatment resistance pose major clinical challenges. In this review, we will present recent findings on the molecular and cellular pathways that are responsible for bone metastasis of PCa. We will address several novel mechanisms with a focus on the role of bone and bone marrow microenvironment in promoting PCa metastasis, and will further discuss why prostate cancer cells preferentially metastasize to the bone. Additionally, we will discuss novel roles of several key pathways, including angiogenesis and extracellular matrix remodeling in bone marrow and stem cell niches with their relationship to PCa bone metastasis and poor treatment response. We will evaluate how various chemotherapeutic drugs and radiation therapies may allow aggressive PCa cells to gain advantageous mutations leading to increased survival and rendering the cancer cells to become resistant to treatment. The novel concept relating several key survival and invasion signaling pathways to stem cell niches and treatment resistance will be reviewed. Lastly, we will provide an update of several recently developed novel drug candidates that target metastatic cancer microenvironments or niches, and discuss the advantages and significance provided by such therapeutic approaches in pursuit of overcoming drug resistance and treating advanced PCa.
| S-EPMC3474961 | biostudies-literature
Project description:BackgroundEpithelial ovarian cancer is the most lethal gynecological cancer and the high mortality is due to the frequent presentation at advanced stage, and to primary or acquired resistance to platinum-based therapy.MethodsWe developed three new models of ovarian cancer patient-derived xenografts (ovarian PDXs) resistant to cisplatin (cDDP) after multiple in vivo drug treatments. By different and complementary approaches based on integrated metabolomics (both targeted and untargeted mass spectrometry-based techniques), gene expression, and functional assays (Seahorse technology) we analyzed and compared the tumor metabolic profile in each sensitive and their corresponding cDDP-resistant PDXs.ResultsWe found that cDDP-sensitive and -resistant PDXs have a different metabolic asset. In particular, we found, through metabolomic and gene expression approaches, that glycolysis, tricarboxylic acid cycle and urea cycle pathways were deregulated in resistant versus sensitive PDXs. In addition, we observed that oxygen consumption rate and mitochondrial respiration were higher in resistant PDXs than in sensitive PDXs under acute stress conditions. An increased oxidative phosphorylation in cDDP-resistant sublines led us to hypothesize that its interference could be of therapeutic value. Indeed, in vivo treatment of metformin and cDDP was able to partially reverse platinum resistance.ConclusionsOur data strongly reinforce the idea that the development of acquired cDDP resistance in ovarian cancer can bring about a rewiring of tumor metabolism, and that this might be exploited therapeutically.
| S-EPMC6591669 | biostudies-literature
Project description:Medulloblastoma (MB) is the most common malignant paediatric brain tumour. Recurrence and progression of disease occurs in 15-20% of standard risk and 30-40% of high risk patients. We analysed whether circumvention of chemoresistance pathways (drug export, DNA repair and apoptotic inhibition) can restore chemotherapeutic efficacy in a panel of MB cell lines.We demonstrate, by immunohistochemistry in patient tissue microarrays, that ABCB1 is expressed in 43% of tumours and is significantly associated with high-risk. We show that ABCB1, O6-methylguanine-DNA-methyltransferase (MGMT) and BCL2 family members are differentially expressed (by quantitative reverse transcription polymerase chain reaction, Western blotting and flow cytometry) in MB cell lines. Based on these findings, each pathway was then inhibited or circumvented and cell survival assessed using clonogenic assays. Inhibition of ABCB1 using vardenafil or verapamil resulted in a significant increase in sensitivity to etoposide in ABCB1-expressing MB cell lines. Sensitivity to temozolomide (TMZ) was MGMT-dependent, but two novel imidazotetrazine derivatives (N-3 sulfoxide and N-3 propargyl TMZ analogues) demonstrated ?7 fold and ?3 fold more potent cytotoxicity respectively compared to TMZ in MGMT-expressing MB cell lines. Activity of the BAD mimetic ABT-737 was BCL2A1 and ABCB1 dependent, whereas the pan-BCL2 inhibitor obatoclax was effective as a single cytotoxic agent irrespective of MCL1, BCL2, BCL2A1, or ABCB1 expression.ABCB1 is associated with high-risk MB; hence, inhibition of ABCB1 by vardenafil may represent a valid approach in these patients. Imidazotetrazine analogues of TMZ and the BH3 mimetic obatoclax are promising clinical candidates in drug resistant MB tumours expressing MGMT and BCL2 anti-apoptotic members respectively.
| S-EPMC4229867 | biostudies-other
Project description:Many modalities of cancer therapy induce mechanisms of treatment resistance and escape pathways during chronic treatments, including photodynamic therapy (PDT). It is conceivable that resistance induced by one treatment might be overcome by another treatment. Emerging evidence suggests that the unique mechanisms of tumor cell and microenvironment damage produced by PDT could be utilized to overcome cancer drug resistance, to mitigate the compensatory induction of survival pathways and even to re-sensitize resistant cells to standard therapies. Approaches that capture the unique features of PDT, therefore, offer promising factors for increasing the efficacy of a broad range of therapeutic modalities. Here, we highlight key preclinical findings utilizing PDT to overcome classical drug resistance or escape pathways and thus enhance the efficacy of many pharmaceuticals, possibly explaining the clinical observations of the PDT response to otherwise treatment-resistant diseases. With the development of nanotechnology, it is possible that light activation may be used not only to damage and sensitize tumors but also to enable controlled drug release to inhibit escape pathways that may lead to resistance or cell proliferation.
| S-EPMC4520758 | biostudies-literature
Project description:Lung cancer is one of the most deadly diseases worldwide. The current first-line therapies include chemotherapy using epidermal growth factor receptor tyrosine kinase inhibitors and radiotherapies. With the current progress in identifying new molecular targets, acquired drug resistance stands as an obstacle for good prognosis. About half the patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor treatments develop resistance. Although extensive studies have been applied to elucidate the underlying mechanisms, evidence is far from enough to establish a well-defined picture to correct resistance. In the review, we will discuss four different currently developed strategies that have the potential to overcome drug resistance in lung cancer therapies and facilitate prolonged anticancer effects of the first-line therapies.
| S-EPMC4057322 | biostudies-literature
Project description:Multidrug resistance (MDR), which significantly decreases the efficacy of anticancer drugs and causes tumor recurrence, has been a major challenge in clinical cancer treatment with chemotherapeutic drugs for decades. Several mechanisms of overcoming drug resistance have been postulated. Well known P-glycoprotein (P-gp) and other drug efflux transporters are considered to be critical in pumping anticancer drugs out of cells and causing chemotherapy failure. Innovative theranostic (therapeutic and diagnostic) strategies with nanoparticles are rapidly evolving and are anticipated to offer opportunities to overcome these limits. In this review, we discuss the mechanisms of drug efflux-mediated resistance and the application of multiple nanoparticle-based platforms to overcome chemoresistance and improve therapeutic outcome.
| S-EPMC3777470 | biostudies-literature