Cancer is one of the major threats to human health. Although humans have struggled with cancer for decades, the efficacy of treatments for most tumors is still very limited. Dihydroartemisinin (DHA) is a derivative of artemisinin, a first-line antimalarial drug originally developed in China. Beyond the anti-malarial effect, DHA has also been reported to show anti-inflammatory, anti-parasitosis, and immune-modulating properties in vitro and in vivo. Furthermore, an increasing number of studies report that DHA possesses anticancer activities on a wide range of cancer types both in vitro and in vivo, as well as enhances the efficacy of chemotherapy, targeted therapy, and even radiotherapy. However, the mechanisms of DHA on different tumors differ in various ways. In this review, we intend to summarize how DHA sensitizes cancer cells to anti-cancer therapies, highlight its molecular mechanisms and pharmacological effects in vitro and in vivo as well as in current clinical trials, and discuss potential issues concerning DHA. Hopefully, more attention will be paid to DHA as a sensitizer for cancer therapy in the future.

Background: Dihydroartemisinin (DHA), a derivate of artemisinin, is an effective antimalarial agent. DHA has been shown to exert anticancer activities to numerous cancer cells in the past few years, while the exact molecular mechanisms remain to be elucidated, especially in esophageal cancer. Methods: Crystal violet assay was conducted to determine the cell viability of human esophageal cancer cell line Eca109 treated with DHA. Tumor-bearing nude mice were employed to evaluate the anticancer effect of DHA in vivo. Soft agar and crystal violet assays were used to measure the tumorigenicity of Eca109 cells. Flow cytometry was performed to evaluate ROS or cell cycle distribution. GFP-LC3 plasmids were delivered into Eca109 cells to visualize autophagy induced by DHA under a fluorescence microscope. The mRNA and protein levels of each gene were tested by qRT-PCR and western blot, respectively. Results: Our results proved that DHA significantly reduced the viability of Eca109 cells in a dose-and time-dependent manner. Further investigation showed that DHA evidently induced cell cycle arrest at the G2/M phase in Eca109 cells. Mechanistically, DHA induced intracellular ROS generation and autophagy in Eca109 cells, while blocking ROS by an antioxidant NAC obviously inhibited autophagy. Furthermore, we found that telomere shelterin component TRF2 was down-regulated in Eca109 cells exposed to DHA through autophagy-dependent degradation, which could be rescued after autophagy was blocked by ROS inhibition. Moreover, the DNA damage response (DDR) was induced obviously in DHA treated cells. To further explore whether ROS or autophagy played a vital role in DHA induced cell cycle arrest, the cell cycle distribution of Eca109 cells was evaluated after ROS or autophagy blocking, and the results showed that autophagy, but not ROS, was essential for cell cycle arrest in DHA treated cells. Conclusion: Taken together, DHA showed anticancer effect on esophageal cancer cells through autophagy-dependent cell cycle arrest at the G2/M phase, which unveiled a novel mechanism of DHA as a chemotherapeutic agent, and the degradation of TRF2 followed by DDR might be responsible for this cell phenotype.

Background Lung adenocarcinoma (LUAD) is the most common dangerous malignant tumor and the leading cause of global cancer incidence and mortality. The Solute Carrier 1A (SLC1A) family play a significant part in cellular biological process, inflammation, and immunity. Specific functions of the SLC1A family in lung cancer are still not systematically described. Objective This study aimed to explore the best biological understanding of SLC1A family in lung cancer. Methods To study the expression and role of the SLC1A family in lung cancer, researchers used a variety of bioinformatics databases and tools. Results Aberrant expression of SLC1A family genes were demonstrated and analyzed the association with gender, tumor grade, cancer stages, and nodal metastasis status. The ectopic expression of SLC1A family genes has prognostic value for LUAD patients. Immune infiltration revealed a significant correlation between SLC1A family genes expression in LUAD. SLC1A family genes were involved in manifold biological processes and have different levels of DNA methylation and genetic alteration. Conclusions These findings suggested that members of the SLC1A family could be a potential target for the development of LUAD therapeutics as well as a reliable indicator of LUAD prognostic value.

Objective: To elucidate the oncogenic role of human telomerase reverse transcriptase (hTERT) in esophageal squamous cancer and unravel the therapeutic role and molecular mechanism of dihydroartemisinin (DHA) by targeting hTERT.Methods: The expression of hTERT in esophageal squamous cancer and the patients prognosis were analyzed by bioinformatic analysis from TCGA database, and further validated with esophageal squamous cancer tissues in our cohort. The Cell Counting Kit-8 (CCK8) and colony formation assay were used to evaluate the proliferation of esophageal squamous cancer cell lines (Eca109, KYSE150, and TE1) after hTERT overexpression or treated with indicated concentrations of DHA. Transwell migration assay and scratch assay were employed to determine the migration abilities of cancer cells. Fluorescence microscopy and flow cytometry were conducted to measure the intracellular reactive oxygen species (ROS) levels in cancer cells after treated with DHA. Moreover, RT-PCR and Western blot were performed to test the alteration of associated genes on mRNA and protein level in DHA treated esophageal squamous cancer cell lines, respectively. Furthermore, tumor-bearing nude mice were employed to evaluate the anticancer effect of DHA in vivo.Results: We found that hTERT was significantly upregulated in esophageal squamous cancer both from TCGA database and our cohort also. Overexpression of hTERT evidently promoted the proliferation and migration of esophageal squamous cancer cells in vitro. Moreover, DHA could significantly inhibit the proliferation and migration of esophageal cancer cell lines Eca109, KYSE150, and TE1 in vitro, and significantly down-regulate the expression of hTERT on both mRNA and protein level in a time- and dose-dependent manner as well. Further studies showed that DHA could induce intracellular ROS production in esophageal cancer cells and down-regulate SP1 expression, a transcription factor that bound to the promoter region of hTERT gene. Moreover, overexpression of SP1 evidently promoted the proliferation and migration of Eca109 and TE1 cells. Intriguingly, rescue experiments showed that inhibiting ROS by NAC alleviated the downregulation of SP1 and hTERT in cells treated with DHA. Furthermore, overexpression of SP1 or hTERT could attenuate the inhibition effect of DHA on the proliferation and migration of Eca109 cells. In tumor-bearing nude mice model, DHA significantly inhibited the growth of esophageal squamous cancer xenografts, and downregulated the expression of SP1 and hTERT protein, while no side effects were observed from heart, kidney, liver, and lung tissues by HE stain.Conclusion: hTERT plays an oncogenic role in esophageal squamous cancer and might be a therapeutic target of DHA through regulating ROS/SP1 pathway.