More than half of cancer patients are treated with radiotherapy, which kills tumor cells by directly and indirectly inducing DNA damage, including cytotoxic DNA double-strand breaks (DSBs). Tumor cells respond to these threats by activating a complex signaling network termed the DNA damage response (DDR). The DDR arrests the cell cycle, upregulates DNA repair, and triggers apoptosis when damage is excessive. The DDR signaling and DNA repair pathways are fertile terrain for therapeutic intervention. This review highlights strategies to improve therapeutic gain by targeting DDR and DNA repair pathways to radiosensitize tumor cells, overcome intrinsic and acquired tumor radioresistance, and protect normal tissue. Many biological and environmental factors determine tumor and normal cell responses to ionizing radiation and genotoxic chemotherapeutics. These include cell type and cell cycle phase distribution; tissue/tumor microenvironment and oxygen levels; DNA damage load and quality; DNA repair capacity; and susceptibility to apoptosis or other active or passive cell death pathways. We provide an overview of radiobiological parameters associated with X-ray, proton, and carbon ion radiotherapy; DNA repair and DNA damage signaling pathways; and other factors that regulate tumor and normal cell responses to radiation. We then focus on recent studies exploiting DSB repair pathways to enhance radiotherapy therapeutic gain.

Cancer is one of the biggest healthcare concerns in our century, a disease whose treatment has become even more difficult following reports of drug-resistant tumors. When this happens, chemotherapy treatments fail or decrease in efficiency, leading to catastrophic consequences to the patient. This discovery, along with the fact that drug resistance limits the efficacy of current treatments, has led to a new wave of discovery for new methods of treatment. The use of nanomedicine has been widely studied in current years as a way to effectively fight drug resistance in cancer. Research in the area of cancer nanotechnology over the past decades has led to tremendous advancement in the synthesis of tailored nanoparticles with targeting ligands that can successfully attach to chemotherapy-resistant cancer by preferentially accumulating within the tumor region through means of active and passive targeting. Consequently, these approaches can reduce the off-target accumulation of their payload and lead to reduced cytotoxicity and better targeting. This review explores some categories of nanocarriers that have been used in the treatment of drug-resistant cancers, including polymeric, viral, lipid-based, metal-based, carbon-based, and magnetic nanocarriers, opening the door for an exciting field of discovery that holds tremendous promise in the treatment of these tumors.

Curcumin, a polyphenol, has a wide range of biological properties such as anticancer, antibacterial, antitubercular, cardioprotective and neuroprotective. Moreover, the anti-proliferative activities of Curcumin have been widely studied against several types of cancers due to its ability to target multiple pathways in cancer. Although Curcumin exhibited potent anticancer activity, its clinical use is limited due to its poor water solubility and faster metabolism. Hence, there is an immense interest among researchers to develop potent, water-soluble, and metabolically stable Curcumin analogs for cancer treatment. While drug resistance remains a major problem in cancer therapy that renders current chemotherapy ineffective, curcumin has shown promise to overcome the resistance and re-sensitize cancer to chemotherapeutic drugs in many studies. In the present review, we are summarizing the role of curcumin in controlling the proliferation of drug-resistant cancers and development of curcumin-based therapeutic applications from cell culture studies up to clinical trials.

Triple Negative Breast Cancer (TNBC) is the most lethal subtype of breast cancer. Despite the successes of emerging targeted therapies, relapse, recurrence, and therapy failure rates in TNBC significantly outpace other subtypes of breast cancer. Mounting evidence suggests accumulation of therapy resistant Cancer Stem Cell (CSC) populations within TNBCs contributes to poor clinical outcomes. These CSCs are enriched in TNBC compared to non-TNBC breast cancers. The mechanisms underlying CSC accumulation have been well-characterized and discussed in other reviews. In this review, we focus on TNBC-specific mechanisms that allow the expansion and activity of self-renewing CSCs. We highlight cellular signaling pathways and transcription factors, specifically enriched in TNBC over non-TNBC breast cancer, contributing to stemness. We also analyze publicly available single-cell RNA-seq data from basal breast cancer tumors to highlight the potential of emerging bioinformatic approaches in identifying novel drivers of stemness in TNBC and other cancers.

Intrinsic or acquired resistance to chemotherapy is a major hurdle in the treatment of cancer. One of the key mechanisms of resistance is the overexpression of the drug efflux transporter P-glycoprotein (Pgp). Pgp overexpression renders a large number of mechanistically unrelated chemotherapies ineffective. Targeting Pgp inhibition directly to overcome drug resistance, although conceptually and mechanistically attractive, has not translated to the clinic, in part because Pgp also has a critical protective function in many healthy tissues. It was recently discovered that carbonic anhydrase XII (CA XII), an enzyme associated with pH regulation in cancer, is co-expressed and co-located with Pgp in drug resistant cancer cells. CA XII is also upregulated by hypoxia, which is another microenvironmental factor that contributes to drug resistance. Here, we review findings that demonstrate modulation of CA XII may offer a promising new approach towards overcoming the longstanding hurdle of drug resistance and therapy failure against solid cancers. This review covers the use of CA XII inhibitors, both small molecule and antibody, in combination with chemotherapeutics that are substrates for Pgp. This combination therapy approach restores the efficacy of chemotherapy in resistant cells and offers a potential new therapeutic window to re-examine the targeting of Pgp as a safe, effective, and novel anticancer strategy.

Most breast cancers are hormone-receptor positive (HR⁺). However, more women eventually die from HR⁺ breast cancer than from either HER2⁺ or triple negative breast cancer. Endocrine therapies continue to be the mainstay of treatment. In 40% of these cases, recurrences in early-stage disease and progression in the metastatic setting are largely a function of the development of endocrine resistance. A multitude of mediators and pathways have been associated with endocrine resistance in breast cancer including the mevalonate pathway, which is integral to cholesterol biosynthesis. The mevalonate pathway and the downstream activation of associated cytoplasmic pathways including PI3K-AKT-mTOR and RAS-MEK-ERK have been known to affect cancer cell proliferation, cell survival, cell invasion, and metastasis. These are important mechanisms leading to the inevitable development of endocrine resistance in HR⁺ breast cancer. Statins are a class of drugs that inhibits HMG-CoA reductase, an enzyme in the mevalonate pathway that plays a central role in cholesterol production. In vitro and in vitro studies suggest that the role of statins in blocking the mevalonate pathway effectively disrupts downstream pathways involved in estrogen receptor expression and cellular processes such as cell survival, proliferation, stress, cell cycle, inhibition of apoptosis, and autophagy. Overcoming these key mechanisms heralds a role for statins in the prevention of endocrine resistance.

Epithelial cancer of the ovary exhibits the highest mortality rate of all gynecological malignancies in women today, since the disease is often diagnosed in advanced stages. While the treatment of cancer with specific chemical agents or drugs is the favored treatment regimen, chemotherapy resistance greatly impedes successful ovarian cancer chemotherapy. Thus, chemoresistance becomes one of the most critical clinical issues confronted when treating patients with ovarian cancer. Convincing evidence hints that dysregulation of E3 ubiquitin ligases is a key factor in the development and maintenance of ovarian cancer chemoresistance. This review outlines recent advancement in our understanding of the emerging roles of E3 ubiquitin ligases in ovarian cancer chemoresistance. We also highlight currently available inhibitors targeting E3 ligase activities and discuss their potential for clinical applications in treating chemoresistant ovarian cancer patients.

Standard small molecule and nanoparticulate chemotherapies are used for cancer treatment; however, their effectiveness remains highly variable. One reason for this variable response is hypothesized to be due to nonspecific drug distribution and heterogeneity of the tumor microenvironment, which affect tumor delivery of the agents. Nanoparticle drugs have many theoretical advantages, but due to variability in tumor microenvironment (TME) factors, the overall drug delivery to tumors and associated antitumor response are low. The nanotechnology field would greatly benefit from a thorough analysis of the TME factors that create these physiological barriers to tumor delivery and treatment in preclinical models and in patients. Thus, there is a need to develop methods that can be used to reveal the content of the TME, determine how these TME factors affect drug delivery, and modulate TME factors to increase the tumor delivery and efficacy of nanoparticles. In this review, we will discuss TME factors involved in drug delivery, and how biomedical imaging tools can be used to evaluate tumor barriers and predict drug delivery to tumors and antitumor response.

DNA direct reversal repair (DRR) is unique in that no DNA synthesis is required to correct the error and therefore repair via such mechanisms are error-free. In humans, DRR is carried out by two different pathways: the O6-methylguanine-DNA methyltransferase (MGMT) and the alkylated DNA repair protein B (AlkB) homologs. The use of alkylating agents is the standard of care for many cancers. However, the use of those drugs is usually halted when resistance develops. This review will examine repair of alkylating agent damage mediated by DRR, resistance mechanisms and potential ways to overcome such resistance.

Oncogenic multidrug resistance (MDR) is a multifactorial phenotype intimately linked to deregulated expression of detoxification transporters. Drug efflux transporters, particularly the MDR P-glycoprotein ABCB1, represent a central mechanism by which not only chemotherapeutic drugs are extruded or sequestered to prevent drug delivery to their intracellular targets, but also for inhibiting apoptotic cell death cues, such as removal of proapoptotic signals. Several cell populations exhibiting the MDR phenotype co-exist within a tumor, such as cells forming the bulk tumor cell mass, cancer stem cells, and cancer persister cells. The key to regulation of ABCB1 expression is the cellular transcriptional machinery. Developmental signaling pathways (e.g, Hedgehog, Notch, Wnt/β-catenin, TGFβ, PITX2) are pivotal in governing cell proliferation, survival, differentiation and guiding cell migration during embryogenesis, and their reactivation during carcinogenesis, which is of particular significance for tumor initiation, progression, and metastasis, also leads to the upregulation of ABCB1. These pathways also drive and maintain cancer cell stemness, for which ABCB1 is used as a marker. In this review, the contribution of canonical and non-canonical developmental signaling pathways in transcriptional regulation of ABCB1 to confer MDR in cancer is delineated.

Intraperitoneal (IP) delivery of cisplatin was developed in the 1970s based on a strong pharmacologic rationale and rodent models. Its advantage over intravenous (IV) administration was supported initially by observational studies in treating recurrent ovarian cancer and eventually by better outcomes from IP vs. IV cisplatin in randomized studies in patients undergoing optimal surgical debulking at diagnosis. In the past two decades, with the introduction of novel anticancer interventions (such as taxanes, bevacizumab, inhibitors of DNA repair, and immune check point inhibitors), advantages of IP drug delivery are less clear and concerns are raised on cisplatin's therapeutic index. The discovery of BRCA genes and their key role in DNA repair, on the other hand, have strengthened the rationale for IP drug delivery: high grade serous cancers arising in the Mullerian epithelium in association with hereditary or somatic BRCA function inactivation are linked to peritoneal spread of cells that - while initially sensitive - are prone to emergence of platinum resistance. Therefore, selection of patients based on genomic features and focusing on the better tolerated IP carboplatin are ongoing. Recent examples of leveraging the peritoneal route include (1) targeting the cell membrane copper transport receptor - that is shared by platinums - by the combination of the proteasome inhibitor bortezomib and IP carboplatin; and (2) enhancing IP 5-fluoro-2-deoxyuridine cytotoxicity when coupled with PARP inhibition.

Aim: Co-encapsulation of anti-cancer agents in pegylated liposomes may provide an effective tool to maximize efficacy of combined drug therapy by taking advantage of the long circulation time, passive targeting, and reduced toxicity of liposome formulations.

Methods: We have developed several liposome formulations of co-encapsulated drugs using various permutations of three active agents: doxorubicin (Dox), mitomycin-C lipidic prodrug (MLP), and alendronate (Ald). Dox and MLP are available in single drug liposomal formulations: pegylated liposomal Dox (PLD, Doxil®), clinically approved, and pegylated liposomal MLP (PL-MLP, Promitil®), in phase 1-2 clinical testing. We have previously shown that co-encapsulation of Dox and Ald in pegylated liposomes (PLAD) results in a formulation with valuable immuno-pharmacologic properties and superior antitumor properties over PLD in immunocompetent animal models. Building on the PLAD and PL-MLP platforms, we developed a new pegylated liposomal formulation of co-entrapped Dox and MLP (PLAD-MLP), with the former localized in the liposome water phase via remote loading with an ammonium alendronate and the latter passively loaded into the liposome lipid bilayer. An alternative formulation of co-entrapped MLP and Dox in which ammonium Ald was replaced with ammonium sulfate (PLD-MLP) was also tested for comparative purposes.

Results: PLAD-MLP displays high loading efficiency of Dox and MLP nearing 100%, and a mean vesicle diameter of 110 nm. Cryo-transmission electron microscopy (cryo-TEM) of PLAD-MLP reveals round vesicles with an intra-vesicle Dox-alendronate precipitate. PLAD-MLP was tested in an in vitro MLP activation assay with the reducing agent dithiothreitol and found to be significantly less susceptible to thiolytic activation than PL-MLP. Alongside thiolytic activation of MLP, a significant fraction of encapsulated Dox was released from liposomes. PLAD-MLP is stable upon in vitro incubation in human plasma with nearly 100% drug retention. In mouse pharmacokinetic studies, PLAD-MLP extended MLP half-life in circulation when compared to that of MLP delivered as PL-MLP. In addition, the MLP levels in tissues were greater than those obtained with PL-MLP, indicating that PLAD-MLP slows down the cleavage of the prodrug MLP to MMC, thus resulting in a more sustained and prolonged exposure. The circulation half-life of Dox in PLAD-MLP was similar to the PLD Dox half-life. The pattern of tissue distribution was similar for the co-encapsulated drugs, although Dox levels were generally higher than those of MLP, as expected from cleavage of MLP to its active metabolite MMC. In mouse tumor models, the therapeutic activity of PLAD-MLP was superior to PL-MLP and PLD with a convenient safety dose window. The Ald-free formulation, PLD-MLP, displayed similar pharmacokinetic properties to PLAD-MLP, but its therapeutic activity was lower.

Conclusion: PLAD-MLP is a novel multi-drug liposome formulation with attractive pharmacological properties and powerful antitumor activity and is a promising therapeutic tool for combination cancer chemotherapy.

Aim: This study investigated the ATP binding cassette (ABC) transporter (ABCA1, ABCB1, ABCB3, ABCC2 and ABCG2) expression in high grade serous ovarian cancer (HGSOC) tissues, cell lines and primary cells to determine their potential relationship with acquired chemotherapy resistance and patient outcome.

Methods: ABC transporter mRNA and protein expression (ABCA1, ABCB1, ABCB3, ABCC2 and ABCG2) was assessed in publicly available datasets and in a tissue microarray (TMA) cohort of HGSOC at diagnosis, respectively. ABC transporter mRNA expression was also assessed in chemosensitive ovarian cancer cell lines (OVCAR-5 and CaOV3) versus matching cell lines with acquired carboplatin resistance and in primary HGSOC cells from patients with chemosensitive disease at diagnosis (n = 10) as well as patients with acquired chemotherapy resistance at relapse (n = 6). The effects of the ABCA1 inhibitor apabetalone in carboplatin-sensitive and -resistant cell lines were also investigated.

Results: High ABCA1 mRNA and protein expression was found to be significantly associated with poor patient outcome. ABCA1 mRNA and protein levels were significantly increased in ovarian cancer cell lines (OVCAR-5 CBPR and CaOV3 CBPR) with acquired carboplatin resistance. ABCA1 mRNA was significantly increased in primary HGSOC cells obtained from patients with acquired chemotherapy resistance. Apabetalone treatment reduced ABCA1 protein expression and increased the sensitivity of both parental and carboplatin-resistant ovarian cancer cells to carboplatin.

Conclusion: These results suggest that inhibiting ABCA1 transporter may be useful in overcoming acquired chemotherapy resistance and improving outcome for patients with HGSOC.

Cancer cells are highly proliferative, invasive, metastatic and initiate angiogenesis. These activities demand plentiful energy and bountiful stores of anabolic precursors, a situation that puts significant strain on metabolic pathways and necessitates juggling of finite resources. However, the location and erratic structural organisation of tumours means they reside in a nutrient-poor environment. The glycolytic phenotype has evolved in cancer cells to provide a suitable balance between bioenergetic and biosynthetic pathways. Does this adopted strategy also support the overexpression of an ATP-dependent transporter (P-glycoprotein) to maintain resistance against chemotherapy? This article highlights the metabolic adaptations used by cancer cells to maintain both a glycolytic phenotype and sustain the activity of P-glycoprotein. We argue that these cells negotiate an energy precipice to achieve these adaptations. Finally, we advocate the use of compounds that place resistant cells expressing P-glycoprotein under further metabolic strain and how uncoupling protein-2 may provide an ideal target for them.