Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes. 

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Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Copper-based metal-organic frameworks for biomedical applications.

Poor targeting of therapeutics leading to severe adverse effects on normal tissues is considered one of the obstacles in cancer therapy. To help overcome this, nanoscale drug delivery systems have provided an alternative avenue for improving the therapeutic potential of various agents and bioactive molecules through the enhanced permeability and retention (EPR) effect. Nanosystems with cancer-targeted ligands can achieve effective delivery to the tumor cells utilizing cell surface-specific receptors, the tumor vasculature and antigens with high accuracy and affinity. Additionally, stimuli-responsive nanoplatforms have also been considered as a promising and effective targeting strategy against tumors, as these nanoplatforms maintain their stealth feature under normal conditions, but upon homing in on cancerous lesions or their microenvironment, are responsive and release their cargoes. In this review, we comprehensively summarize the field of active targeting drug delivery systems and a number of stimuli-responsive release studies in the context of emerging nanoplatform development, and also discuss how this knowledge can contribute to further improvements in clinical practice. 

/pdf/enhancing-the-therapeutic-efficacy-of-nanoparticles-for-16hldfnu.pdf

Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies

A specific-targeted nanomodulator capable of manipulating tumor microenvironment against metastasis.

Simple Summary In recent decades, scientific discoveries brought up several new treatments and improvements for patients suffering from hepatocellular carcinoma (HCC). However, increasing resistance to current therapies, such as sorafenib, worsen the outcome of HCC patients, leading to a search for alternative therapeutic strategies. The term ferroptosis describes a novel form of regulated cell death, which is different from apoptosis and necroptosis in a mechanistical and morphological manner. The main mechanism, which leads to cell death, is lipid peroxidation, caused by iron overload and the accumulation of polyunsaturated fatty acids. Recent studies demonstrate that ferroptosis can hamper the carcinogenesis in several tumor entities and in HCC. Therefore, a better understanding and a deeper insight in the processes of ferroptosis in HCC and the possible application of it in the clinical practice are of extreme importance. Abstract Ferroptosis, an iron and reactive oxygen species (ROS)-dependent non-apoptotic type of regulated cell death, is characterized by a massive iron overload and peroxidation of polyunsaturated fatty acids (PUFAs), which finally results in cell death. Recent studies suggest that ferroptosis can influence carcinogenesis negatively and therefore may be used as a novel anti-cancer strategy. Hepatocellular carcinoma (HCC) is a deadly malignancy with poor chances of survival and is the second leading cause of cancer deaths worldwide. Diagnosis at an already late stage and general resistance to current therapies may be responsible for the dismal outcome. As the liver acts as a key factor in iron metabolism, ferroptosis is shown to play an important role in HCC carcinogenesis and, more importantly, may hold the potential to eradicate HCC. In this review, we summarize the current knowledge we have of the role of ferroptosis in HCC and the application of ferroptosis as a therapy option and provide an overview of the potential translation of ferroptosis in the clinical practice of HCC.

/pdf/ferroptosis-in-hepatocellular-carcinoma-mechanisms-drug-3d5aquju.pdf

Hai-Long Tian

Papers

A cascaded copper-based nanocatalyst by modulating glutathione and cyclooxygenase-2 for hepatocellular carcinoma therapy