Heng Luo

RECQL4 as a novel drug target against ovarian cancer

Ovarian cancer is characterized by poor specificity and unfavorable prognosis. Therefore, exploring new mechanisms of ovarian cancer development, identifying specific new targets, and developing effective therapeutic drugs based on these new targets have become the focus of current research. This study collected clinical case tissues from high-grade serous ovarian cancer (HGSC) patients and found that the expression of RecQ-like helicase 4 (RECQL4) was positively correlated with the malignancy of ovarian cancer but negatively correlated with its prognosis. From the chemical library of traditional Chinese medicine and ethnic medicines established by our research group in Guizhou, we screened out an effective target, a fluorinated tanshinone analogue (TC12-1), which can effectively inhibit and bind to RECQL4. In vitro experiments showed that TC12-1 induced apoptosis and inhibited cancer cell invasion and metastasis. Additionally, TC12-1 can induce DNA damage, enhancing replication fork stress and blocking the cell cycle at the S phase in cancer cells. The compound effectively inhibited tumor growth and metastasis in subcutaneous tumor models and in orthotopic ovarian cancer mouse models, showing no significant toxicity to vital organs in tumor animal models. The molecular mechanism of TC12-1 targeting RECQL4 in anti-ovarian epithelial cell carcinoma involves the regulation of key genes such as γ-H2AX, PRPA32, ATM, RAD50, CHK2, P53, P21, Bax, Cyclin E, and CDC2, thereby affecting the cell cycle and DNA replication signaling pathways. The results provide theoretical support for developing specific ovarian cancer therapeutic drugs using RECQL4 as a new target.

Trifluoromethyl quinoline derivative targets inhibiting HDAC1 for promoting the acetylation of histone in cervical cancer cells

Cervical cancer is the leading cause of death among gynecological malignant tumors, especially due to the poor prognosis of patients with advanced tumors due to recurrence, metastasis, and chemotherapy resistance. Therefore, exploring new antineoplastic drugs with high efficacy and low toxicity may bring new expectations in patients with cervical cancer. Natural products and their derivatives exert an antitumor activity. Therefore, in this work, combined with network pharmacology analysis and experimental validation, we investigated the anti-cervical cancer activity and molecular mechanism of a new trifluoromethyl quinoline (FKL) derivative in vivo and in vitro. FKL117 inhibited the proliferation of cervical cancer cells in a dose and time-dependent manner, induced apoptosis in HeLa cells, arrested the cell cycle in the G2/M phase, and regulated the expression of the apoptotic and cell cycle-related proteins Bcl-2, Bax, cyclin B1, and CDC2. We used online databases to obtain HDAC1 as one of the possible targets of FKL117 and the target binding and binding affinity were modeled by molecular docking. The results showed that FKL117 formed a hydrogen bond with HDAC1 and had good binding ability. We found that FKL117 targeted to inhibit the expression and function of HDAC1 and increased the acetylation of histone H3 and H4, which was also confirmed in vivo. The migration of HMGB1 from the nucleus to the cytoplasm further verified the above results. In conclusion, our study suggested that FKL117 might be used as a novel candidate for targeting the inhibition of HDAC1 against cervical cancer.