Rational Design of Selenadiazole Derivatives to Antagonize Hyperglycemia‐Induced Drug Resistance in Cancer Cells

Hyperglycemia is an important factor for chemoresistance of hepatocellular carcinoma patients with diabetes to therapeutics. In the present study, a series of selenadiazole derivatives have been rationally designed, synthesized, and found be able to antagonize drug resistance in HepG2 cells to doxorubicin (DOX) under simulated diabetes conditions. Hyperglycemia could promote the cell proliferation through upregulation of ERK and AKT phosphorylation. However, the synthetic selenadiazole derivatives effectively potentiated the cellular uptake of DOX and enhanced the antiproliferative activity of DOX on HepG2 cells by induction of apoptosis, via regulation of ROS‐mediated AMPK activation, inhibition of mTORC1, and an increase in DNA damage. The selenadiazole derivatives that possess an increased lipophilicity could enhance the cellular uptake and anticancer efficacy of DOX. Taken together, this study provides a rational design strategy of selenadiazole derivatives to overcome hyperglycemia‐induced drug resistance.     

Targeted Therapy of B7 Family Checkpoints as an Innovative Approach to Overcome Cancer Therapy Resistance: A Review from Chemotherapy to Immunotherapy

It is estimated that there were 18.1 million cancer cases worldwide in 2018, with about 9 million deaths. Proper diagnosis of cancer is essential for its effective treatment because each type of cancer requires a specific treatment procedure. Cancer therapy includes one or more approaches such as surgery, radiotherapy, chemotherapy, and immunotherapy. In recent years, immunotherapy has received much attention and immune checkpoint molecules have been used to treat several cancers. These molecules are involved in regulating the activity of T lymphocytes. Accumulated evidence shows that targeting immune checkpoint regulators like PD-1/PD-L1 and CTLA-4 are significantly useful in treating cancers. According to studies, these molecules also have pivotal roles in the chemoresistance of cancer cells. Considering these findings, the combination of immunotherapy and chemotherapy can help to treat cancer with a more efficient approach. Among immune checkpoint molecules, the B7 family checkpoints have been studied in various cancer types such as breast cancer, myeloma, and lymphoma. In these cancers, they cause the cells to become resistant to the chemotherapeutic agents. Discovering the exact signaling pathways and selective targeting of these checkpoint molecules may provide a promising avenue to overcome cancer development and therapy resistance. Highlights: (1) The development of resistance to cancer chemotherapy or immunotherapy is the main obstacle to improving the outcome of these anti-cancer therapies. (2) Recent investigations have described the involvement of immune checkpoint molecules in the development of cancer therapy resistance. (3) In the present study, the molecular participation of the B7 immune checkpoint family in anticancer therapies has been highlighted. (4) Targeting these immune checkpoint molecules may be considered an efficient approach to overcoming this obstacle.     

基于NMR的绒癌化疗耐药机制的代谢组学研究

绒癌是一种发生于育龄妇女的恶性滋养细胞肿瘤.经甲氨蝶呤、5-氟尿嘧啶等单药或多药联合化疗后,其治愈率通常高达90%.然而耐药仍是绒癌治疗失败的主要原因.目前绒癌耐药的机制尚不明确,前人多从蛋白和转录水平阐述,鲜有涉及代谢物层次的研究.本文采用基于核磁共振（NMR）的代谢组学方法,研究了甲氨蝶呤耐药株JEG3R与敏感株JEG3绒癌细胞及其培养基在代谢物水平上的差异.结果发现JEG3R耐药极可能与糖代谢异常相关,主要表现为耐药株细胞中山梨糖醇的累积,提示醛糖还原酶可能在耐药过程中起重要作用;其次,耐药株细胞中乳酸积累、丙氨酸流入三羧酸循环途径增强;此外,耐药株细胞相比敏感株细胞中氨基酸、核苷酸及磷酸胆碱等必需营养物质的显著性改变,且其变化与绒癌增殖速率正相关.本研究为绒癌的耐药机制研究补充了代谢层次的数据,为后续从分子生物学水平上揭示耐药机制提供了新思路.     

Epithelial–Mesenchymal Transition-Mediated Tumor Therapeutic Resistance

Cancer is one of the world’s most burdensome diseases, with increasing prevalence and a high mortality rate threat. Tumor recurrence and metastasis due to treatment resistance are two of the primary reasons that cancers have been so difficult to treat. The epithelial–mesenchymal transition (EMT) is essential for tumor drug resistance. EMT causes tumor cells to produce mesenchymal stem cells and quickly adapt to various injuries, showing a treatment-resistant phenotype. In addition, multiple signaling pathways and regulatory mechanisms are involved in the EMT, resulting in resistance to treatment and hard eradication of the tumors. The purpose of this study is to review the link between EMT, therapeutic resistance, and the molecular process, and to offer a theoretical framework for EMT-based tumor-sensitization therapy.     

Lipid Droplets in Cancer: From Composition and Role to Imaging and Therapeutics

Cancer is the second most common cause of death worldwide, having its origin in the abnormal growth of cells. Available chemotherapeutics still present major drawbacks, usually associated with high toxicity and poor distribution, with only a small fraction of drugs reaching the tumour sites. Thus, it is urgent to develop novel therapeutic strategies. Cancer cells can reprogram their lipid metabolism to sustain uncontrolled proliferation, and, therefore, accumulate a higher amount of lipid droplets (LDs). LDs are cytoplasmic organelles that store neutral lipids and are hypothesized to sequester anti-cancer drugs, leading to reduced efficacy. Thus, the increased biogenesis of LDs in neoplastic conditions makes them suitable targets for anticancer therapy and for the development of new dyes for cancer cells imaging. In recent years, cancer nanotherapeutics offered some exciting possibilities, including improvement tumour detection and eradication. In this review we summarize LDs biogenesis, structure and composition, and highlight their role in cancer theranostics.     

Copper(II) Phenanthroline-Based Complexes as Potential AntiCancer Drugs: A Walkthrough on the Mechanisms of Action

Copper is an endogenous metal ion that has been studied to prepare a new antitumoral agent with less side-effects. Copper is involved as a cofactor in several enzymes, in ROS production, in the promotion of tumor progression, metastasis, and angiogenesis, and has been found at high levels in serum and tissues of several types of human cancers. Under these circumstances, two strategies are commonly followed in the development of novel anticancer Copper-based drugs: the sequestration of free Copper ions and the synthesis of Copper complexes that trigger cell death. The latter strategy has been followed in the last 40 years and many reviews have covered the anticancer properties of a broad spectrum of Copper complexes, showing that the activity of these compounds is often multi factored. In this work, we would like to focus on the anticancer properties of mixed Cu(II) complexes bearing substituted or unsubstituted 1,10-phenanthroline based ligands and different classes of inorganic and organic auxiliary ligands. For each metal complex, information regarding the tested cell lines and the mechanistic studies will be reported and discussed. The exerted action mechanisms were presented according to the auxiliary ligand/s, the metallic centers, and the increasing complexity of the compound structures.     

Regulating Mitochondrial pH with Light and Implications for Chemoresistance

Chemoresistance is one of the major challenges for cancer treatment, more recently ascribed to defective mitochondrial outer membrane permeabilization (MOMP), significantly diminishing chemotherapeutic agent-induced apoptosis. A boron-dipyrromethene (BODIPY) chromophore-based triarylsulfonium photoacid generator (BD-PAG) was used to target mitochondria with the aim to regulate mitochondrial pH and further depolarize the mitochondrial membrane. Cell viability assays demonstrated the relative biocompatibility of BD-PAG in the dark while live cell imaging suggested high accumulation in mitochondria. Specific assays indicated that BD-PAG is capable of regulating mitochondrial pH with significant effects on mitochondrial membrane depolarization. Therapeutic tests using chlorambucil in combination with BD-PAG revealed a new strategy in chemoresistance suppression.