Novel insights into histone lysine methyltransferases in cancer therapy:From epigenetic regulation to selective drugs

The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune microenvironment.Therapeutically,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple malignancies.In this review,we have updated recent understandings of KMTs'functions and the development of their targeted inhibitors.First,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and immune regulation.In addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors.In summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.

Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors:mechanisms and strategies

Immunotherapies based on immune checkpoint blockade(ICB)have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade.To date,immune checkpoint inhibitors(ICIs)of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy.Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers,however,a large subset of refractory patients presents poor responsiveness to ICB therapy;and the underlying mechanism remains elusive.Recently,numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment(TME)with various products of metabolism,and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy.Nevertheless,a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance.Here,we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints(CTLA-4,PD-1,and PD-L1)to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

Calcium carbonate-doxorubicin @silica-indocyanine green nanospheres with photo-triggered drug delivery enhance cell killing in drug-resistant breast cancer cells

Calcium carbonate-doxorubicin@silica-indocyanine green nanospheres with high uniformity and monodispersity were designed and synthesized, in order to provide a photo-triggered strategy for drug-resistant cancer therapy. Under near-infrared laser irradiation, the nanospheres transformed laser power into local heat and reactive oxygen species via the connected indocyanine green molecule, thus exhibiting photothermal and photodynamic effects. Moreover, the photo-triggered drug release based on calcium-assisted silica degradation was observed, endowing the nanospheres with chemotherapeutic properties. Finally, combined therapeutic effects against drug-resistant human breast cancer cells were successfully obtained. These photo-triggered materials based on calcium carbonate could provide a promising platform for enhanced multimodal cancer therapies.

THERAPEUTIC EFFECTS OF PHOTOSENSITIZERS IN COMBINATION WITH LASER AND ACNU ON AN IN VIVO OR IN VITROMODEL OF CEREBRAL GLIOMA

This study investigated the independent and combined effects of photodynamic therapy (PDT), laser photodynamic hyperthermia (LPDH) and 1-(4-amino-2-methyl-5-pyrimidinyl) methy1-3-(2-chloroethyl) -3-nitrosourea hydrochloride (ACNU) in a rat 9L induced gliosarcoma model. The mortality rate (MR60), mean survival time (MST60), and increasing life span (ILS60) within 60 days were determined to evaluate the therapeutic effect in vivo. The MR60 and MST60 of the gliosarcoma tumor control were 100% and 16.2 days. The ILS60s of PDT and ACNU were 72.84% and 49.81%, respectively, but MR60 of both were 86.72%. All combined treatments produced significantly prolonged survival (P<0.01). The combined effects of LPDH and ACNU, MR60, MST60, and ILS60 were 60%, 43 days, and 165.4%, respectively. The ILS60 of PDT+ACNU (96.48%) and PDT+LPDH (98.58%) also indicated a synergistic or additive effect. The survival fraction and synthetic rate of DNA, RNA, and protein of glioma 9L tumor cells in vitro after single treatment of PDT or combined with antitumor drugs and laser showed that the cytotoxicity of PDT to 9L tumor cell was obvious by using Rh123, HPD, and Pf-Ⅱ as photosensitizers. Combined treatments of PDT, antitumor drugs, and laser suppressed the synthesis of DNA, RNA, and protein more significantly than single treatment with PDT.