Docetaxel (DTX) chemotherapy offers excellent initial response and confers significant survival benefit in patients with castration-resistant prostate cancer (CRPC). However, the clinical utility of DTX is compromised when primary and acquired resistance are encountered. Therefore, a more thorough understanding of DTX resistance mechanisms may potentially improve survival in patients with CRPC. This review focuses on DTX and discusses its mechanisms of resistance. We outline the involvement of tubulin alterations, androgen receptor (AR) signaling/AR variants, ERG rearrangements, drug efflux/influx, cancer stem cells, centrosome clustering, and phosphoinositide 3-kinase/AKT signaling in mediating DTX resistance. Furthermore, potential biomarkers for DTX treatment and therapeutic strategies to circumvent DTX resistance are reviewed.
The poor prognosis of glioblastoma multiforme (GBM) patients is in part due to resistance to current standard-of-care treatments including chemotherapy [predominantly temozolomide (TMZ; Temodar)], radiation therapy and an anti-angiogenic therapy [an antibody against the vascular endothelial growth factor (bevacizumab; Avastin)], resulting in recurrent tumors. Several recurrent GBM tumors are commonly resistant to either TMZ, radiation or bevacizumab, which contributes to the low survival rate for GBM patients. This review will focus on novel targets and therapeutic approaches that are currently being considered to combat GBM chemoresistance. One of these therapeutic options is a small molecule called OKlahoma Nitrone 007 (OKN-007), which was discovered to inhibit the transforming growth factor β1 pathway, reduce TMZ-resistance and enhance TMZ-sensitivity. OKN-007 is currently an investigational new drug in clinical trials for both newly-diagnosed and recurrent GBM patients. Another novel target is ELTD1 (epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1; alternatively known as ADGRL4, Adhesion G protein-coupled receptor L4), which we used a monoclonal antibody against, where a therapy against it was found to inhibit Notch 1 in a pre-clinical GBM xenograft model. Notch 1 is known to be associated with chemoresistance in GBM. Other potential therapeutic targets to combat GBM chemoresistance include the phosphoinositide 3-kinase pathway, nuclear factor-κB, the hepatocyte/scatter factor (c-MET), the epidermal growth factor receptor, and the tumor microenvironment.
Pancreatic cancer is one of the most aggressive cancers with a high mortality rate even among patients with early-stage disease. Although recent studies with novel therapeutic approaches have led to modest improvement in survival outcomes, limited progress is achieved for the use of immunotherapeutics in this challenging cancer. Immune checkpoint inhibitors, thus far, single-agent or in combination, have not yielded significant improvement in survival outcomes except in mismatch repair-deficient pancreatic cancer. The tumor microenvironment of pancreatic cancer has been considered as an attractive target for over a decade based on preclinical studies that suggested it may adversely affect drug delivery and antitumor immunity. In this review article, we elaborate on the biology of pancreatic cancer microenvironment, its highly complicated interaction with cancer cells, and the immune system. We also discuss plausible explanations that led to the failure of immune checkpoint inhibitors as therapeutic agents and the potential impacts of pancreatic cancer stroma on these negative studies.
Pulmonary carcinomas have developed mechanisms by which they escape the attack of immune cells. Immune checkpoint molecules programmed death 1 - programmed death ligand 1 (PD1-PDL1) and the cytotoxic T-lymphocyte antigen 4 system have gained attention. The expression of PDL1 by tumor cells causes immune tolerance, and further influences the microenvironment via orchestration by cytokines. Therapy with PDL1 antibodies could restore the cytotoxicity of T-lymphocytes towards tumor cells. Many patients will respond to this treatment. However, resistance mechanisms will counteract this therapy. New investigations have identified additional immune checkpoint inhibitors such as lymphocyte activation gene 3 and T cell immunoglobulin and mucin-domain containing-3. Tumor cells also induce tolerance by manipulating cells of the innate immune system. Macrophages are polarized to tumor-friendly M2, neutrophils into N2 types, and dendritic cells and myeloid suppressor cells are switched to assist tumor cells. Regulatory T cells enter the tumor microenvironment and signal tolerance to cytotoxic cells, inhibiting the influx of NK cells. Soluble mediators either released by tumor cells or cells of the tumor stroma induce immune tolerance, examples including tryptophan and indolamine dioxygenases, arginine and adenosine. Treatment options to counteract these molecules are currently being tested. The tumor stroma has been classified as immune-inflamed, immune-excluded, and immune-desert types. The latter might be switched to an inflamed type by induction of tertiary lymph follicles. Dendritic cells and macrophages normally phagocytose tumor antigens, but inhibitors of phagocytosis can block this. Interference with these molecules is another option for re-establishing the cytotoxic action of the immune system against tumor cells. In this review we will discuss these aspects with a special emphasis on non-small cell lung cancer.
In recent years, many therapeutic advances have been made in the management of castration-resistant prostate cancer, with the development and approval of many new drugs. The androgen receptor (AR) is the main driver in prostate cancer growth and progression and the most effective therapeutic agents are still directed against this pathway. Among these, new generation hormonal agents (NHA) including enzalutamide, abiraterone acetate, apalutamide, and darolutamide have shown to improve overall survival and quality of life of prostate cancer patients. Unfortunately, despite the demonstrated benefit, not all patients respond to treatment and almost all are destined to develop a resistant phenotype. Although the resistance mechanisms are not fully understood, the most studied ones include the activation of both dependent and independent AR signalling pathways. Recent findings about multiple growth-promoting and survival pathways in advanced prostate cancer suggest the presence of alternative mechanisms involved in disease progression, and an interplay between these pathways and AR signalling. In this review we discuss the possible mechanisms of primary and acquired resistance to NHA with a focus on AR independent pathways.
Androgen deprivation therapy targeting the androgens/androgen receptor (AR) signaling continues to be the mainstay treatment of advanced-stage prostate cancer. The use of second-generation antiandrogens, such as abiraterone acetate and enzalutamide, has improved the survival of prostate cancer patients; however, a majority of these patients progress to castration-resistant prostate cancer (CRPC). The mechanisms of resistance to antiandrogen treatments are complex, including specific mutations, alternative splicing, and amplification of oncogenic proteins resulting in dysregulation of various signaling pathways. In this review, we focus on the major mechanisms of acquired resistance to second generation antiandrogens, including AR-dependent and AR-independent resistance mechanisms as well as other resistance mechanisms leading to CRPC emergence. Evolving knowledge of resistance mechanisms to AR targeted treatments will lead to additional research on designing more effective therapies for advanced-stage prostate cancer.
At the forefront of cancer research is the rapidly evolving understanding of metabolic reprogramming within cancer cells. The expeditious adaptation to metabolic inhibition allows cells to evolve and acquire resistance to targeted treatments, which makes therapeutic exploitation complex but achievable. 3-phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme of de novo serine biosynthesis and is highly expressed in a variety of cancers, including breast cancer, melanoma, and Ewing’s sarcoma. This review will investigate the role of PHGDH in normal biological processes, leading to the role of PHGDH in the progression of cancer. With an understanding of the molecular mechanisms by which PHGDH expression advances cancer growth, we will highlight the known mechanisms of resistance to cancer therapeutics facilitated by PHGDH biology and identify avenues for combatting PHGDH-driven resistance with inhibitors of PHGDH to allow for the development of effective metabolic therapies.
Incidences of head and neck squamous cell carcinoma (HNSCC) have been on the rise in the last few decades, with a significant risk factor being human papillomavirus (HPV) type-16/18 infection, particularly in the development of oropharyngeal cancers. Radiotherapy (RT) is an important treatment modality for HNSCC, where it promotes extensive cellular DNA damage leading to the therapeutic effect. It has been well-established that HPV-positive HNSCC display better response rates and improved survival following RT compared to HPV-negative HNSCC. The differential radiosensitivity has been largely associated with altered cellular DNA damage response mechanisms in HPV-positive HNSCC, and particularly with the signaling and repair of DNA double strand breaks. However, other factors, particularly hypoxia present within the solid cancer, have a major impact on relative radioresistance. Consequently, recent approaches aimed at enhancing the radiosensitivity of HNSCC have largely centered on targeting key proteins involved in DNA repair, DNA damage checkpoint activation, and hypoxia signaling. These studies have utilised in vitro and in vivo models of HPV-positive and HPV-negative HNSCC and examined the impact of specific inhibitors against the targets in combination with radiation in suppressing HNSCC cell growth and survival. Here, accumulating evidence has shown that targeting enzymes including poly (ADP-ribose) polymerase, ataxia telangiectasia and Rad-3 related, DNA-dependent protein kinase catalytic subunit, and checkpoint kinase 1 can radiosensitise HNSCC cells which should be taken forward in further preclinical studies, with the goal of optimizing the future effective RT treatment of HNSCC.
Epigenetic regulation refers to alterations to the chromatin template that collectively establish differential patterns of gene transcription. Post-translational modifications of the histones play a key role in epigenetic regulation of gene transcription. In this review, we provide an overview of recent studies on the role of histone modifications in carcinogenesis. Since tumour-selective ligands such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) are well-considered as promising anti-tumour therapies, we summarise strategies for improving TRAIL sensitivity by inhibiting aberrant histone modifications in cancers. In this perspective we also discuss new epigenetic drug targets for enhancing TRAIL-mediated apoptosis.
Prostate cancer is a condition commonly associated with men worldwide. Androgen deprivation therapy remains one of the targeted therapies. However, after some years, there is biochemical recurrence and metastatic progression into castration-resistant prostate cancer (CRPC). CRPC cases are treated with second-line androgen deprivation therapy, after which, these CRPCs transdifferentiate to form neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. NEPC arises via a reversible transdifferentiation process, known as neuroendocrine differentiation (NED), which is associated with altered expression of lineage markers such as decreased expression of androgen receptor and increased expression of neuroendocrine lineage markers including enolase 2, chromogranin A and synaptophysin. The etiological factors and molecular basis for NED are poorly understood, contributing to a lack of adequate molecular biomarkers for its diagnosis and therapy. Therefore, there is a need to fully understand the underlying molecular basis for this cancer. Recent studies have shown that microRNAs (miRNAs) play a key epigenetic role in driving therapy-induced NED in prostate cancer. In this review, we briefly describe the role of miRNAs in prostate cancer and CRPCs, discuss some key players in NEPCs and elaborate on miRNA dysregulation as a key epigenetic process that accompanies therapy-induced NED in metastatic CRPC. This understanding will contribute to better clinical management of the disease.
Gemcitabine is a cytidine analogue frequently used in the treatment of various cancers. However, the development of chemoresistance limits its effectiveness. Gemcitabine resistance is regulated by various factors, including aberrant genetic and epigenetic controls, metabolism of gemcitabine, the microenvironment, epithelial-to-mesenchymal transition, and acquisition of cancer stem cell properties. In many situations, results using cell lines offer valuable lessons leading to the first steps of important findings. In this review, we mainly discuss the factors involved in gemcitabine metabolism in association with chemoresistance, including nucleoside transporters, deoxycytidine kinase, cytidine deaminase, and ATP-binding cassette transporters, and outline new perspectives for enhancing the efficacy of gemcitabine to overcome acquired chemoresistance.
Epithelial-mesenchymal plasticity (EMP) of cancer cells contributes to cancer cell heterogeneity, and it is well established that EMP is a critical determinant of acquired resistance to cancer treatment modalities including radiation therapy, chemotherapy, and targeted therapies. Here, we aimed to explore how EMP contributes to cancer cell camouflage, allowing an ever-changing population of cancer cells to pass under the radar of our immune system and consequently compromise the effect of immune checkpoint blockade therapies. The ultimate clinical benefit of any combination regimen is evidenced by the sum of the drug-induced alterations observed in the variety of cellular populations composing the tumor immune microenvironment. The finely-tuned molecular crosstalk between cancer and immune cells remains to be fully elucidated, particularly for the spectrum of malignant cells along the epithelial to mesenchymal axis. High-dimensional single cell analyses of specimens collected in ongoing clinical studies is becoming a key contributor to our understanding of these interactions. This review will explore to what extent targeting EMP in combination with immune checkpoint inhibition represents a promising therapeutic avenue within the overarching strategy to reactivate a halting cancer-immunity cycle and establish a robust host immune response against cancer cells. Therapeutic strategies currently in clinical development will be discussed.
Nanodiamonds represent an attractive potential carrier for anticancer drugs. The main advantages of nanodiamond particles with respect to medical applications are their high compatibility with non-cancerous cells, feasible surface decoration with therapeutic and cancer-cell targeting molecules, and their relatively low manufacturing cost. Additionally, nanodiamond carriers significantly increase treatment efficacy of the loaded drug, so anticancer drugs execute more effectively at a lower dose. Subsequently, lower drug dose results in less extensive side effects. The carriers decorated with a targeting molecule accumulate primarily in the tumor tissue, and those nanodiamond particles impair efflux of the drug from cancer cells. Therapeutic approaches considering nanodiamond carriers were already tested in vitro, as well as in vivo. Now, researchers focus particularly on the possible side effects of nanodiamond carriers applied systemically in vivo. The behavior of nanodiamond carriers depends heavily on their surface coatings, so each therapeutic complex must be evaluated separately. Generally, it seems that site-specific application of nanodiamond carriers is a rather safe therapeutic approach, but intravenous application needs further study. The benefits of nanodiamond carriers are remarkable and represent a potent approach to overcome the drug resistance of many cancers.
Indoles of cruciferous vegetables are promising anti-tumor agents. Studies with indole-3-carbinol and its dimeric product, 3,3’-diindolylmethane (DIM), suggest that these compounds have the ability to deregulate multiple cellular signaling pathways that are essential for tumor growth and spread. These natural compounds are also effective modulators of transcription factors and non-coding RNAs. These effects explain their ability to inhibit tumor spread and to overcome drug resistance. In this work, pertinent literature on the effects of DIM and its synthetic derivatives on resistant tumors and resistance mechanisms in tumors is highlighted.
Nanotechnology-based drug delivery platforms have been developed over the last two decades because of their favorable features in terms of improved drug bioavailability and stability. Despite recent advancement in nanotechnology platforms, this approach still falls short to meet the complexity of biological systems and diseases, such as avoiding systemic side effects, manipulating biological interactions and overcoming drug resistance, which hinders the therapeutic outcomes of the NP-based drug delivery systems. To address these issues, various strategies have been developed including the use of engineered cells and/or cell membrane-coated nanocarriers. Cell membrane receptor profiles and characteristics are vital in performing therapeutic functions, targeting, and homing of either engineered cells or cell membrane-coated nanocarriers to the sites of interest. In this context, we comprehensively discuss various cell- and cell membrane-based drug delivery approaches towards cancer therapy, the therapeutic potential of these strategies, and the limitations associated with engineered cells as drug carriers and cell membrane-associated drug nanocarriers. Finally, we review various cell types and cell membrane receptors for their potential in targeting, immunomodulation and overcoming drug resistance in cancer.
Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor (AR) signaling. Current therapies use AR signaling inhibitors (ARSI) exemplified by abiraterone acetate, a P450c17 inhibitor, and enzalutamide, a potent AR antagonist. However, drug resistance to these agents occurs within 12-18 months and they only prolong overall survival by 3-4 months. Multiple mechanisms can contribute to ARSI drug resistance. These mechanisms can include but are not limited to germline mutations in the AR, post-transcriptional alterations in AR structure, and adaptive expression of genes involved in the intracrine biosynthesis and metabolism of androgens within the tumor. This review focuses on intracrine androgen biosynthesis, how this can contribute to ARSI drug resistance, and therapeutic strategies that can be used to surmount these resistance mechanisms.
Circumvention of cancer drug resistance is one of the major investigations in nanomedicine. In this regard, nanotechnology-based drug delivery has offered various implications. However, protein-based nanocarriers have been a versatile choice compared to other nanomaterials, provided by their favorable characteristics and safety profiles. Specifically, albumin-based nanoparticles have been demonstrated to be an effective drug delivery system, owing to the inherent targeting modalities of albumin, through gp60- and SPARC-mediated receptor endocytosis. Furthermore, surface functionalization was exploited for active targeting, due to albumin’s abundance of carboxylic and amino groups. Stimuli-responsive drug release has also been pertained to albumin nano-systems. Therefore, albumin-based nanocarriers could potentially overcome cancer drug resistance through bypassing drug efflux, enhancing drug uptake, and improving tumor accumulation. Moreover, albumin nanocarriers improve the stability of various therapeutic cargos, for instance, nucleic acids, which allows their systemic administration. This review highlights the recent applications of albumin nanoparticles to overcome cancer drug resistance, the nano-fabrication techniques, as well as future perspectives and challenges.
Aim: Liver cancer is one of the most common malignancies and has a high recurrence rate. However, current treatment strategies do not achieve satisfactory outcomes in the clinic. To explore a new strategy to enhance the effectiveness of chemotherapy in liver cancer, we investigated whether dichloroacetate (DCA) could enhance the sensitivity of liver cancer cells to pirarubicin (THP).
Methods: Liver cancer cells were treated with DCA alone, THP alone, or DCA and THP combined. Cell viability was determined by the CCK-8 assay. Cell apoptosis was analyzed by flow cytometer. Reactive oxygen species (ROS) were detected using a CM-H2DCFDA fluorescence probe. Protein levels were identified by immunoblotting.
Results: The results revealed that DCA significantly enhanced the antitumor effect of THP in liver cancer cells. Changes in morphology and adherence ability were observed, as well as decreased cell viability. The results of flow cytometry showed that the combination of THP and DCA significantly increased apoptosis of liver cancer cells. Moreover, compared with THP alone, combination treatment with DCA significantly increased THP-triggered ROS generation in liver cancer cells. The antioxidant N-acetyl-L-cysteine reversed the synergistic effect of DCA and THP on ROS generation, cell viability and apoptosis. Furthermore, phosphorylation of c-Jun N-terminal kinase (JNK) was significantly increased in the DCA and THP combination group. The effects of DCA and THP on cell viability and apoptosis were inhibited by the JNK inhibitor SP600125.
Conclusion: The results obtained in the present study indicated that DCA enhanced the antitumor effect of THP in liver cancer cells via regulating the ROS-JNK signaling pathway.
Aim: Despite considerable efforts to reverse clinical multidrug resistance (MDR), targeting the predominant multidrug transporter ABCB1/P-glycoprotein (P-gp) using small molecule inhibitors has been unsuccessful, possibly due to the emergence of alternative drug resistance mechanisms. However, the non-specific P-gp inhibitor cyclosporine (CsA) showed significant clinical benefits in patients with acute myeloid leukemia (AML), which likely represents the only proof-of-principle clinical trial using several generations of MDR inhibitors. Nevertheless, the mutational mechanisms that may underlie unsuccessful MDR modulation by CsA are not elucidated because of the absence of CsA-relevant cellular models. In this study, our aims were to establish CsA-resistant leukemia models and to examine the presence or absence of ABCB1 exonic mutations in these models as well as in diverse types of human cancer samples including AMLs.
Methods: Drug-resistant lines were established by stepwise drug co-selection and characterized by drug sensitivity assay, rhodamine-123 accumulation, [3H]-labeled drug export, ABCB1 cDNA sequencing, and RNase protection assay. The genomic stability of the ABCB1 coding regions was evaluated by exome sequencing analysis of variant allele frequencies in human populations. Moreover, the mutational spectrum of ABCB1 was further assessed in diverse types of cancer samples including AMLs in the Cancer Genome Atlas (TCGA) at the National Cancer Institute.
Results: We report the development of two erythroleukemia variants, RVC and RDC, which were derived by stepwise co-selection of K562/R7 drug-resistant leukemia cells with the etoposide-CsA and doxorubicin-CsA drug combinations, respectively. Interestingly, both RVC and RDC cell lines, which retained P-gp expression, showed altered multidrug-resistant phenotypes that were resistant to CsA modulation. Strikingly, no mutations were found in the ABCB1 coding regions in these variant cells even under long-term stringent drug selection. Genomically, ABCB1 displayed relatively low variant allele frequencies in human populations when compared with several ABC superfamily members. Moreover, ABCB1 also exhibited a very low mutational frequency in AMLs compared with all types of human cancer. In addition, we found that CsA played a role in undermining the selection of highly drug-resistant cells via induction of low-level and unstable drug resistance.
Conclusion: Our data indicate that ABCB1 coding regions are genomically stable and relatively resistant to drug-induced mutations. Non-ABCB1 mutational mechanisms are responsible for the drug-resistant phenotypes in both RVC and RDC cell lines, which are also prevalent in clinical AML patients. Accordingly, we propose several relevant models that account for the development of alternative drug resistance mechanisms in the absence of ABCB1 mutations.
Aim: Innate resistance to the CHK1 inhibitor prexasertib has been described, but resistance mechanisms are not understood. We aimed to determine the role epidermal growth factor receptor (EGFR) plays in innate resistance to prexasertib in triple negative breast cancer (TNBC).
Methods: Using a panel of pre-clinical TNBC cell lines, we measured the sensitivity to prexasertib. We examined the effect activation of EGFR had on prexasertib sensitivity. We measured the synergy of dual blockade of EGFR with erlotinib and CHK1 with prexasertib in TNBC cell lines and xenografts.
Results: EGFR overexpression and activation increased resistance to CHK1 inhibition by prexasertib. EGFR promoted the phosphorylation of BCL2-associated agonist of cell death (BAD), inactivating its pro-apoptotic functions. Inhibition of EGFR reversed BAD phosphorylation, increasing sensitivity to prexasertib.
Conclusion: The use of prexasertib as a monotherapy in TNBC has been limited due to modest clinical responses. We demonstrated that EGFR activation contributes to innate resistance to prexasertib in TNBC and potentially other cancers. EGFR expression status should be considered in clinical trials examining prexasertib’s use as a monotherapy or combination therapy.
Well-differentiated thyroid carcinoma (WDTC, including papillary thyroid carcinoma and follicular thyroid carcinoma) are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery and postoperative radioiodine therapy. Subsets of WDTCs may dedifferentiate into poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), of which especially the latter has an exceptionally poor patient outcome. The underlying genetics responsible for this tumor progression is only partly understood, and is complicated by the fact that subgroups of ATCs are thought to arise de novo without a demonstrable, pre-existing WDTC. Even so, recent advances using next generation sequencing (NGS) techniques have identified a genetic link between WDTCs and ATCs, suggesting a step-wise accumulation of mutations driving the loss of differentiation for most cases. In this Commentary, recent findings from an NGS study on synchronous FTC, PDTC, and ATC tumor components from the same patient are highlighted. By using whole-genome data, clonality analyses identified a chief ancestral clone carrying mutations in TP53-associated signaling networks regulating genes involved in DNA repair, with sub-clones in each tumor component that were identified also in the less differentiated, neighboring tumor. Moreover, mutational signatures suggested a general mismatch repair (MMR) deficiency along with microsatellite instability. These findings support the chained progression model of dedifferentiation in thyroid cancer, and pinpoint a central role for defective DNA repair. Since effective treatment modalities for ATCs are urgently needed, studies regarding therapeutic agents specifically targeting defective MMR in dedifferentiated thyroid carcinoma could be pursued.
Every year, cancer accounts for a vast portion of deaths worldwide. Established clinical protocols are based on chemotherapy, which, however, is not tumor-selective and produces a series of unbearable side effects in healthy tissues. As a consequence, multidrug resistance (MDR) can arise causing metastatic progression and disease relapse. Combination therapy has demonstrated limited responses in the treatment of MDR, mainly due to the different pharmacokinetic properties of administered drugs and to tumor heterogeneity, challenges that still need to be solved in a significant percentage of cancer patients. In this perspective, we briefly discuss the most relevant MDR mechanisms leading to therapy failure and we report the most advanced strategies adopted in the nanomedicine field for the design and evaluation of ad hoc nanocarriers. We present some emerging classes of nanocarriers developed to reverse MDR and discuss recent progress evidencing their limits and promises.
Ovarian cancer has the highest mortality rate among gynecologic malignancies. The combination of cytoreductive surgery and chemotherapy is the standard regimen for the treatment of ovarian cancer. The initial treatment is usually effective, but many patients with ovarian cancer experience recurrence, and treatment options for recurrent disease remain challenging. Cancer stem cells (CSCs) are suggested to play an essential role in cancer recurrence after initial chemotherapy. Furthermore, they are of great interest as CSCs may also be involved in chemotherapy susceptibility. Thus, understanding the characteristics and mechanisms by which CSCs display resistance to therapeutic agents is important to design effective cancer treatments. In this review, we describe and discuss current therapeutic regimens for ovarian cancer, as well as the various CSC markers, association between CSCs and disease progression, correlation of CSCs with poor prognosis, enrichment of CSCs in tumor tissues following repeated chemotherapy cycles, activation of major signaling pathways following chemotherapy, and potential inhibitors that suppress these signaling cascades. In addition, clinical trials evaluating novel targeted therapies to overcome chemotherapy resistance will be reviewed. The combination of traditional chemotherapy and CSC-targeted therapy could be an effective and promising anticancer treatment for ovarian cancer. Understanding the biological properties of CSCs and the mechanism of chemotherapy resistance are critical to design and develop new therapeutic strategies to overcome CSC-associated chemotherapy resistance.