Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway

Ovarian cancer is a carcinoma that affects women and that has a high mortality rate. Overcoming paclitaxel resistance is important for clinical application. However, the effect of amino acid metabolism regulation on paclitaxel-resistant ovarian cancer is still unknown. In this study, the effect of an amino acid-deprived condition on paclitaxel resistance in paclitaxel-resistant SKOV3-TR cells was analyzed. We analyzed the cell viability of SKOV3-TR in culture conditions in which each of the 20 amino acids were deprived. As a result, the cell viability of the SKOV3-TR was significantly reduced in cultures deprived of arginine, glutamine, and lysine. Furthermore, we showed that the glutamine-deprived condition inhibited mTORC1/S6K signaling. The decreased cell viability and mTORC1/S6K signaling under glutamine-deprived conditions could be restored by glutamine and α-KG supplementation. Treatment with PF-4708671, a selective S6K inhibitor, and the selective glutamine transporter ASCT2 inhibitor V-9302 downregulated mTOR/S6K signaling and resensitized SKOV3-TR to paclitaxel. Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer.     

Crosstalk between Ca2+ Signaling and Cancer Stemness: The Link to Cisplatin Resistance

In the fight against cancer, therapeutic strategies using cisplatin are severely limited by the appearance of a resistant phenotype. While cisplatin is usually efficient at the beginning of the treatment, several patients endure resistance to this agent and face relapse. One of the reasons for this resistant phenotype is the emergence of a cell subpopulation known as cancer stem cells (CSCs). Due to their quiescent phenotype and self-renewal abilities, these cells have recently been recognized as a crucial field of investigation in cancer and treatment resistance. Changes in intracellular calcium (Ca²⁺) through Ca²⁺ channel activity are essential for many cellular processes such as proliferation, migration, differentiation, and survival in various cell types. It is now proved that altered Ca²⁺ signaling is a hallmark of cancer, and several Ca²⁺ channels have been linked to CSC functions and therapy resistance. Moreover, cisplatin was shown to interfere with Ca²⁺ homeostasis; thus, it is considered likely that cisplatin-induced aberrant Ca²⁺ signaling is linked to CSCs biology and, therefore, therapy failure. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to a range of pressures dictates the global degree of cisplatin resistance. However, if we can understand the molecular mechanisms linking Ca²⁺ to cisplatin-induced resistance and CSC behaviors, alternative and novel therapeutic strategies could be considered. In this review, we examine how cisplatin interferes with Ca²⁺ homeostasis in tumor cells. We also summarize how cisplatin induces CSC markers in cancer. Finally, we highlight the role of Ca²⁺ in cancer stemness and focus on how they are involved in cisplatin-induced resistance through the increase of cancer stem cell populations and via specific pathways.     

Tissue-Engineering the Fibrous Pancreatic Tumour Stroma Capsule in 3D Tumouroids to Demonstrate Paclitaxel Response

Pancreatic cancer is a unique cancer in that up to 90% of its tumour mass is composed of a hypovascular and fibrotic stroma. This makes it extremely difficult for chemotherapies to be delivered into the core of the cancer mass. We tissue-engineered a biomimetic 3D pancreatic cancer (“tumouroid”) model comprised of a central artificial cancer mass (ACM), containing MIA Paca-2 cells, surrounded by a fibrotic stromal compartment. This stromal compartment had a higher concentration of collagen type I, fibronectin, laminin, and hyaluronic acid (HA) than the ACM. The incorporation of HA was validated with alcian blue staining. Response to paclitaxel was determined in 2D MIA Paca-2 cell cultures, the ACMs alone, and in simple and complex tumouroids, in order to demonstrate drug sensitivity within pancreatic tumouroids of increasing complexity. The results showed that MIA Paca-2 cells grew into the complex stroma and invaded as cell clusters with a maximum distance of 363.7 µm by day 21. In terms of drug response, the IC₅₀ for paclitaxel for MIA Paca-2 cells increased from 0.819 nM in 2D to 3.02 nM in ACMs and to 5.87 nM and 3.803 nM in simple and complex tumouroids respectively, indicating that drug penetration may be significantly reduced in the latter. The results demonstrate the need for biomimetic models during initial drug testing and evaluation.     

The Role of Exosomal Non-Coding RNAs in Colorectal Cancer Drug Resistance

Background: Colorectal cancer (CRC) is one of the most common types of cancer diagnosed worldwide with high morbidity; drug resistance is often responsible for treatment failure in CRC. Non-coding RNAs (ncRNAs) play distinct regulatory roles in tumorigenesis, cancer progression and chemoresistance. Methods: A literature search was conducted in PubMed database in order to sum up and discuss the role of exosomal ncRNAs (ex-ncRNAs) in CRC drug resistance/response and their possible mechanisms. Results: Thirty-six (36) original research articles were identified; these included exosome or extracellular vesicle (EV)-containing microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and small-interfering (siRNAs). No studies were found for piwi-interacting RNAs. Conclusions: Exosomal transfer of ncRNAs has been documented as a new mechanism of CRC drug resistance. Despite being in its infancy, it has emerged as a promising field for research in order to (i) discover novel biomarkers for therapy monitoring and/or (ii) reverse drug desensitization.     

Implication of microRNAs in Carcinogenesis with Emphasis on Hematological Malignancies and Clinical Translation

MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs, that are involved in the multistep process of carcinogenesis, contributing to all established hallmarks of cancer. In this review, implications of miRNAs in hematological malignancies and their clinical utilization fields are discussed. As components of the complex regulatory network of gene expression, influenced by the tissue microenvironment and epigenetic modifiers, miRNAs are “micromanagers” of all physiological processes including the regulation of hematopoiesis and metabolic pathways. Dysregulated miRNA expression levels contribute to both the initiation and progression of acute leukemias, the metabolic reprogramming of malignantly transformed hematopoietic precursors, and to the development of chemoresistance. Since they are highly stable and can be easily quantified in body fluids and tissue specimens, miRNAs are promising biomarkers for the early detection of hematological malignancies. Besides novel opportunities for differential diagnosis, miRNAs can contribute to advanced chemoresistance prediction and prognostic stratification of acute leukemias. Synthetic oligonucleotides and delivery vehicles aim the therapeutic modulation of miRNA expression levels. However, major challenges such as efficient delivery to specific locations, differences of miRNA expression patterns between pediatric and adult hematological malignancies, and potential side effects of miRNA-based therapies should be considered.     

Curcumin: A Novel Way to Improve Quality of Life for Colorectal Cancer Patients?

Colorectal cancer (CRC) is the third most common cancer in men and the second most common in women. Treatment of metastatic CRC consists of highly toxic chemotherapeutic drug combinations that often negatively affect patient quality of life (QoL). Moreover, chemotherapy-induced toxicity and chemotherapy resistance are among the most important factors limiting cancer treatment and can lead to the interruption or discontinuation of potentially effective therapy. Several preclinical studies have demonstrated that curcumin acts through multiple cellular pathways and possesses both anti-cancer properties against CRC and the capacity to mitigate chemotherapy-related side effects and overcome drug resistance. In this review article, we suggest that the addition of curcumin to the standard chemotherapeutic treatment for metastatic CRC could reduce associated side-effects and overcome chemotherapy resistance, thereby improving patient QoL.     

Comprehensive Evaluation of Multiple Approaches Targeting ABCB1 to Resensitize Docetaxel-Resistant Prostate Cancer Cell Lines

Docetaxel (DTX) is a mainstay in the treatment of metastatic prostate cancer. Failure of DTX therapy is often associated with multidrug resistance caused by overexpression of efflux membrane transporters of the ABC family such as the glycoprotein ABCB1. This study investigated multiple approaches targeting ABCB1 to resensitize DTX-resistant (DTXR) prostate cancer cell lines. In DU145 DTXR and PC-3 DTXR cells as well as age-matched parental controls, the expression of selected ABC transporters was analyzed by quantitative PCR, Western blot, flow cytometry and immunofluorescence. ABCB1 effluxing activity was studied using the fluorescent ABCB1 substrate rhodamine 123. The influence of ABCB1 inhibitors (elacridar, tariquidar), ABCB1-specific siRNA and inhibition of post-translational glycosylation on DTX tolerance was assessed by cell viability and colony formation assays. In DTXR cells, only ABCB1 was highly upregulated, which was accompanied by a strong effluxing activity and additional post-translational glycosylation of ABCB1. Pharmacological inhibition and siRNA-mediated knockdown of ABCB1 completely resensitized DTXR cells to DTX. Inhibition of glycosylation with tunicamycin affected DTX resistance partially in DU145 DTXR cells, which was accompanied by a slight intracellular accumulation and decreased effluxing activity of ABCB1. In conclusion, DTX resistance can be reversed by various strategies with small molecule inhibitors representing the most promising and feasible approach.