Current Medicinal Chemistry - Volume 32, Issue 2, 2025

Skin cancer, a common malignancy worldwide, has increased incidence and mortality. Thus, it is a public health issue and a significant illness burden, which increases treatment costs. Chemotherapy and surgery are used to treat skin cancer. However, conventional skin cancer treatments have several limitations, demanding the development of innovative, safe, and effective methods. To overcome these limitations of conventional topical dosage forms, many nanocarriers have been developed and tested for the targeted delivery of anticancer drugs.

The main objective of the present review was to discuss the utility of various vesicular nanocarrier systems to deliver anticancer drugs following topical administration to treat skin cancer.

For this review article, we scoured the scholarly literature using Science Direct, Google Scholar, and PubMed.

The vesicular drug delivery system has been intensively explored and developed as an alternative to conventional skin cancer drug delivery systems, especially for melanoma. They improve the penetration of anticancer drugs via the skin, reaching the cancer area with enough and killing cancer cells. Vesicles minimize skin irritation and drug degradation. This improves therapy efficacy and reduces systemic toxicity.

Utilizing the vesicular drug delivery system shows promise in treating skin cancer. Therefore, further research and inquiries are necessary to explore the therapeutic potential of these substances in treating skin cancer, intending to develop a personalized, efficient, and secure therapy approach for patients with this condition.

The proteins CDK4 and CDK6, which are extremely homologous, control cell cycle entry. For the treatment of breast tumors that include hormone receptors, CDK4 and CDK6 inhibitors have been authorized. The link between CDK4 and liver hepatocellular carcinoma (LIHC), however, has not yet been established.

The study aimed to explore the link between CDK4 and LIHC and the effect of CDK4 inhibitors on LIHC.

In this study, we have evaluated CDK4's prognostic relevance in LIHC using data from The Cancer Genome Atlas (TCGA). The relationship between clinical-pathologic features and CDK4 expression has been evaluated using the Kruskal-Wallis test, the Wilcoxon signed-rank test, and logistic regression. We have analyzed CDK4 and factors related to the prognosis of HCC using the Kaplan-Meier technique and multivariate Cox regression. Gene set enrichment analysis (GSEA) identified CDK4-related critical pathways. To investigate the connections between CDK4 and cancer immune infiltrates, TCGA data were employed in single-sample gene set enrichment analysis (ssGSEA). For functional validation, CDK4 was chosen since it can be inhibited by recognized CDK4/6-inhibitors (e.g., abemaciclib).

Poorer overall and disease-specific outcomes were linked to high CDK4 expression in HCC patients. GSEA suggested that CDK4 and immune response are closely connected. The amount of Th2 cells infiltrating was positively correlated with CDK4 expression, while the amount of cytotoxic cells infiltrating was negatively correlated, according to ssGSEA. Both in vitro and in vivo, the anti-tumor efficacy of CDK4 inhibitor has been found to be superior to that of sorafenib.

This study suggests a relationship between CDK4 and immune infiltration and prognosis in HCC. Additionally, a CDK4 inhibitor may have anti-tumor properties against hepatocellular cancer.

Oral squamous cell carcinoma (OSCC) represents the primary form of oral cancer, posing a significant global health threat. The existing chemotherapy options are accompanied by notable side effects impacting patient treatment adherence. Consequently, the exploration and development of novel substances with enhanced anticancer effects and fewer side effects have become pivotal in the realms of biological and chemical science.

This work presents the pioneering examples of naphthoquinone-coumarin hybrids as a new category of highly effective cytotoxic substances targeting oral squamous cell carcinoma (OSCC).

Given the significance of both naphthoquinones and coumarins as essential pharmacophores/privileged structures in the quest for anticancer compounds, this study focused on the synthesis and evaluation of novel naphthoquinones/coumarin hybrids against oral squamous cell carcinoma.

By several in vitro, in silico, and in vivo approaches, we demonstrated that compound 6e was highly cytotoxic against OSCC cells and several other cancer cell types and was more selective than current chemotherapeutic drugs (carboplatin) and the naphthoquinone lapachol. Furthermore, compound 6e was non-hemolytic and tolerated in vivo at 50 mg/kg with an LD50 of 62.5 mg/kg. Furthermore, compound 6e did not induce apoptosis and cell cycle arrest but led to intracellular vesicle formation with LC3 aggregation in autophagosomes, suggesting an autophagic cell death. Additionally, 6e had a high-affinity potential for PKM2 protein, higher than the known ligands, such as lapachol or shikonin, and was able to inhibit this enzyme activity in vitro.

We assert that compound 6e shows promise as a potential lead for a novel chemotherapeutic drug targeting OSCC, with potential applicability to other cancer types.

Developing effective methods to enhance tumor radiosensitivity is crucial for improving the therapeutic efficacy of radiotherapy (RT). Due to its deep tissue penetration, excellent safety profile, and precise controllability, sonosensitizer-based sonodynamic therapy (SDT) has recently garnered significant attention as a promising combined approach with RT.

However, the limited reactive oxygen species (ROS) generation ability in the aggregated state and the absence of specific organelle targeting in sonosensitizers hinder their potential to augment RT. This study introduces a fundamental principle guiding the design of high-performance sonosensitizers employed in the aggregated state. Building upon these principles, we develop a mitochondria-targeted sonosensitizer molecule (TCSVP) with aggregation-induced emission (AIE) characteristics by organic synthesis. Then, we demonstrate the abilities of TCSVP to target mitochondria and produce ROS under ultrasound in H460 cancer cells using confocal laser scanning microscopy (CLSM) and fluorescence microscopy. Subsequently, we examine the effectiveness of enhancing tumor radiosensitivity by utilizing TCSVP and ultrasound in both H460 cells and H460 and 4T1 tumor-bearing mice.

The results indicate that evoking non-lethal mitochondrial oxidative stress in tumors by TCSVP under ultrasound stimulation can significantly improve tumor radiosensitivity (p <0.05). Additionally, the in vivo safety profile of TCSVP is thoroughly confirmed by histopathological analysis.

This work proposes strategies for designing efficient sonosensitizers and underscores that evoking non-lethal mitochondrial oxidative stress is an effective method to enhance tumor radiosensitivity.