Drug resistance remains a major challenge in cancer treatment, necessitating the development of novel strategies to overcome it. Protein arginine methyltransferases (PRMTs) are enzymes responsible for epigenetic arginine methylation, which regulates various biological and pathological processes, as a result, they are attractive therapeutic targets for overcoming anti-cancer drug resistance. The ongoing development of small molecules targeting PRMTs has resulted in the generation of chemical probes for modulating most PRMTs and facilitated clinical treatment for the most advanced oncology targets, including PRMT1 and PRMT5. In this review, we summarize various mechanisms underlying protein arginine methylation and the roles of specific PRMTs in driving cancer drug resistance. Furthermore, we highlight the potential clinical implications of PRMT inhibitors in decreasing cancer drug resistance. PRMTs promote the formation and maintenance of drug-tolerant cells via several mechanisms, including altered drug efflux transporters, autophagy, DNA damage repair, cancer stem cell-related function, epithelial-mesenchymal transition, and disordered tumor microenvironment. Multiple preclinical and ongoing clinical trials have demonstrated that PRMT inhibitors, particularly PRMT5 inhibitors, can sensitize cancer cells to various anti-cancer drugs, including chemotherapeutic, targeted therapeutic, and immunotherapeutic agents. Combining PRMT inhibitors with existing anti-cancer strategies will be a promising approach for overcoming anti-cancer drug resistance. Furthermore, enhanced knowledge of the complex functions of arginine methylation and PRMTs in drug resistance will guide the future development of PRMT inhibitors and may help identify new clinical indications.

Malignant melanoma is the most fatal form of skin cancer worldwide, and earlier diagnosis and more effective therapies are required to improve prognosis. As a possible solution, near-infrared fluorescent heptamethine cyanine dyes have been shown to be useful for tumor diagnosis and treatment. Here, we synthesized a novel theranostic agent, IR-817, a multifunctional bioactive small-molecule that has near-infrared emission, targets mitochondria in cancer cells, and has selective anti-cancer effects. In in vitro experiments, IR-817 preferentially accumulated in melanoma cells through organic anion transporting polypeptide transporters but also selectively inhibited the growth of tumor cells by inducing mitochondrial-dependent intrinsic apoptosis. Mechanistically, IR-817 caused G0/G1 cell cycle arrest by targeting the E2F/Cyclin/CDK pathway. Finally, IR-817 significantly suppressed the growth of xenograft tumors in zebrafish and mice. Immunohistochemical staining and hematoxylin and eosin staining revealed that IR-817 induced apoptosis and inhibited tumor cell proliferation without notable side effects. Therefore, mitochondrial-targeting theranostic agent IR-817 may be promising for accurate tumor diagnosis, real-time monitoring, and safe anti-cancer treatments.

The increased drug resistance and metastasis of melanoma resulted in poor prognosis of patients. Here, we designed and synthesized a novel hemicyanine-based fluorescent probe ZWZ-3, and investigated its application for melanoma imaging and treatment both in vitro and in vivo. ZWZ-3 preferentially accumulated in melanoma cells via a process that depended on the organic anion-transporting polypeptide (OATP), which targeted mitochondria on the hemicyanine cationic nitrogen. In addition, we investigated the effect and molecular mechanism of ZWZ-3 in melanoma. In vitro studies showed that ZWZ-3 promoted the generation of reactive oxygen species and induced mitochondrial-mediated cell apoptosis by upregulating Bax and activating caspase-3, caspase-9, and PARP. Importantly, ZWZ-3 also induced autophagy by upregulating LC-3II and Atg5 and downregulating P62. It significantly suppressed tumor growth of A375 xenograft tumor in mice without notable side effects. Histological and immunohistochemical analyses revealed that ZWZ-3 induced apoptosis and inhibited tumor cell proliferation. Thus, ZWZ-3 represents a novel theranostic agent that can be used to effectively targeting, detecting, and treating melanoma. It could also help monitoring disease progression and response to treatment.

Background: Near-infrared cyanine dyes have high sensitivity and spatial resolution imaging capabilities, but they also have unavoidable drawbacks such as photobleaching, low water solubility, fluorescence quenching, and toxic side effects. As an effective biologic drug carrier, albumin combines with cyanine dyes to form albumin@dye nanoparticles. These nanoparticles can alleviate the aforementioned issues and are widely used in tumor imaging and photothermal therapy. Methods: Herein, a newly synthesized near-infrared dye IR-817 was combined with bovine serum albumin (BSA) to create BSA@IR-817 nanoparticles. Through the detection of fluorescence emission and absorption, the optimal concentration and ratio of BSA and IR-817 were determined. Subsequently, dynamic light scattering (DLS) measurements and scanning electron microscopy (SEM) were used for the physical characterization of the BSA@IR-817 nanoparticles. Finally, in vitro and in vivo experiments were conducted to assess the fluorescence imaging and photothermal therapeutic potential of BSA@IR-817 nanoparticles. Results: IR-817 was adsorbed onto the BSA carrier by covalent conjugation and supramolecular encapsulation, resulting in the formation of dispersed, homogeneous, and stable nanoparticles with a particle size range of 120-220 nm. BSA@IR-817 not only improved the poor water solubility, fluorescence quenching, and toxic side effects of IR-817 but also enhanced the absorption and fluorescence emission peaks in the near-infrared region, as well as the fluorescence in the visible spectrum. In addition, BSA@IR-817 combined with laser 808 irradiation was able to convert light energy into heat energy with temperatures exceeding 50 degrees C. By creating a mouse model of subcutaneous melanoma, it was discovered that the tumor inhibition rate of BSA@IR-817 was greater than 99% after laser irradiation and that it achieved nearly complete tumor ablation without causing significant toxicity. Conclusion: Our research, therefore, proposes the use of safe and effective photothermal nanoparticles for the imaging, diagnosis, and treatment of melanoma, and offers a promising strategy for future biomedical applications.