Current Medicinal Chemistry - Volume 30, Issue 16, 2023

Background: Although chemotherapy is predominantly used for cancer treatment, it can be ineffective and can induce serious side effects and lead to chemoresistance. It is essential to discover novel drugs that can enhance the antitumor activity and at the same time, counteract the severe side effects, of chemotherapy. The substance P (SP)/neurokinin-1 receptor (NK-1R) interaction system is known to play a key role in the pathogenesis of cancer. Studies with NK-1R antagonists (such as aprepitant) denote that the NK-1R is a potential target for the treatment of cancer. Aprepitant combined with major chemotherapeutic drugs has shown the potential to increase antitumor activity and decrease side effects. Objective: Since malignant tumor cancer cells overexpress the NK-1R, this combination therapy is a promising approach for the treatment of all kinds of cancer. Since aprepitant shows potential of being a broad-antitumor drug, the repurposing of this NK-1R antagonist as an antitumor agent is warranted. Studies pertaining to combination therapy of aprepitant/radiotherapy will also be outlined in this review. The aim of this review is to provide an update on combinational studies pertaining to chemotherapy/radiotherapy and NK-1R antagonist in cancer. Conclusion: This combination strategy once confirmed, might open the door to a new era in chemotherapy and radiotherapy with greater antitumor activity and fewer side effects. This treatment strategy could possibly translate into higher cure rates, better quality of life and fewer sequelae in cancer patients.

Cysteine (Cys) is a semi-essential nutrient amino acid that plays an important role in cells through endogenous production and various transport systems. Intracellular Cys can be used as a precursor of protein synthesis to maintain cell homeostasis and to generate sulfur-containing substances, including glutathione (GSH), hydrogen sulfide (H2S), and taurine. There have been quite a few reports that Cys is related to tumor occurrence and development, and its level is closely related to tumor proliferation, invasion, and metastasis. Moreover, it helps in maintaining the tumor redox balance and increasing drug resistance. This review aims to summarize the production and metabolism of Cys and its role in tumors, with special emphasis on the potential therapeutic value of Cys in tumors to improve the quality of life of cancer patients.

Background: STAT3 (signal transducer and activator of transcription 3) is a member of the STAT family of proteins that function as signal transducers and transcription factors. Previous research has demonstrated its importance in cell proliferation, differentiation, apoptosis, and immunological and inflammatory responses. Targeting the STAT3 protein has recently been hailed as a viable cancer therapeutic method. Even though none of these inhibitors have yet been exploited in clinical cancer therapy, a small number have made them into clinical trials, leading researchers to explore more promising inhibitors. Methods: Based on the mechanism of STAT3 activation, several types of STAT3 inhibitors were described and summarized according to their origins, structures, bioactivity and mechanism of action. Direct inhibition of STAT3 mainly targeted one of the three distinct structural regions of the protein, namely the SH2 domain, the DNA binding domain, and the coiled-coil domain. Results: The progress in STAT3 inhibitor discovery from 2010 to 2021 is comprehensively summarized in this review. STAT3 inhibitors are mainly classified into small molecule inhibitors, natural product inhibitors, and peptides/peptidomimetics. Moreover, it also covers relevant analogues, as well as their core framework. Conclusion: Small-molecule inhibitors of STAT3 like BP-1-102 and BTP analogues displayed great potential against various cancers, while natural products, as well as peptide and peptidomimetics, also showed promising application. Therefore, STAT3 has become a promising target with great research value, and the development of STAT3 inhibitors may provide more therapeutic strategies for STAT3-related diseases.

Ferroptosis is an iron-dependent cell death, characterized by the accumulation of lipid-reactive oxygen species; various regulatory mechanisms influence the course of ferroptosis. The rapid increase in cardiovascular diseases (CVDs) is an extremely urgent problem. CVDs are characterized by the progressive deterioration of the heart and blood vessels, eventually leading to circulatory system disorder. Accumulating evidence, however, has highlighted crucial roles of ferroptosis in CVDs. Hydrogen sulfide plays a significant part in anti-oxidative stress, which may participate in the general mechanism of ferroptosis and regulate it by some signaling molecules. This review has primarily summarized the effects of hydrogen sulfide on ferroptosis and cardiovascular disease, especially the antioxidative stress, and would provide a more effective direction for the clinical study of CVDs.

Long-term diabetes can lead to renal injury known as diabetic nephropathy (DN), which is a major cause of end-stage renal disease (ESRD). However, its pathogenesis has not been well explained. Adipose tissue is recognized as an important energy storage device for the body. Interestingly, many studies have shown that adipose tissue can also act as an endocrine organ by secreting a variety of adipokines to maintain homeostasis. Here, we summarize some of the adipokines that have been identified so far to, more specifically, emphasize their role in DN progression and propose that the “adipose-renal axis” may be a potential target for treating DN.

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and one of the main causes of end-stage renal disease (ESRD). There are many factors causing the progression of DN. Lipid metabolism disorder is a common clinical manifestation of DN, and ectopic renal lipid deposition was recently proposed as a key factor promoting the development of DN. Lipophagy is a newly discovered type of selective autophagy that can remove excessive lipids in cells to maintain lipid homeostasis. Recently, abnormalities in lipophagy have also been implicated in the progression of DN. Here, we discuss the formation of lipid droplets, describe lipophagy and its key regulatory signals, summarize the current research progress of lipophay in DN, and finally propose that lipophagy may be a potential target for the treatment of DN.

Autophagy is the process by which cells selectively remove damaged organelles or proteins. Chaperone-mediated autophagy (CMA) is a type of autophagy that degrades proteins containing the KFERQ pentapeptide in cells. CMA can degrade damaged or excess proteins and therefore plays an important role in maintaining protein balance in cells. CMA can also play a regulatory role by degrading key proteins in life activities, such as lipid and glucose metabolism. This review introduces the CMA process and describes the current commonly used CMA detection methods. In addition, we describe the role of CMA in glucose and lipid metabolism. Finally, we summarize the current role of CMA in metabolic diseases such as diabetic nephropathy (DN), alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) and discuss the role of CMA as a potential therapeutic target for metabolic diseases.