morphinans and Uterine-Cervical-Neoplasms

Overexpression of thioredoxin reductase (TrxR) has been linked to tumorigenesis and phenotypic maintenance of malignant tumors. Thus, targeting TrxR with natural molecules is a promising strategy for developing anticancer drugs. Sinomenine is a naturally occurring alkaloid isolated from Sinomenium acutum. The drug, Zhengqing Fengtongning made from sinomenine, has been universally applied in rheumatoid arthritis treatment in China as well as other Asian countries for decades. Recently, increasing evidence indicates that sinomenine appears to be a promising therapeutic agent against various cancer cells. However, the exact mechanism underlying the anticancer activity of sinomenine remains unclear. In this study, we identified sinomenine as a kind of new inhibitor for TrxR. Pharmacological inhibition of TrxR by sinomenine results in the decrease of thiols content, increases the levels of reactive oxygen species, and finally facilitates oxidative stress-mediated cancer cell apoptosis. It is vital that knockdown in TrxR1 by shRNA can increase cell sensitivity to sinomenine. Treatment with sinomenine in vivo leads to a decrease in TrxR activity and tumor growth, and an increase in apoptosis. Our findings provide a novel action mechanism related to sinomenine and presents an insight on how to develop sinomenine as a chemotherapeutic agent for cancer therapy.

Topics: Antirheumatic Agents; Apoptosis; Drug Repositioning; Female; Humans; Morphinans; Reactive Oxygen Species; Thioredoxin-Disulfide Reductase; Uterine Cervical Neoplasms

The use of plant‑based compounds derived from traditional medicine to improve human diseases has been gaining momentum, due to their high bioavailability and moderate adverse effects. Sinomenine is one such biomonomer alkali compound derived from Sinomenium acutum and is known for its anti‑inflammatory and antitumor effects. However, the molecular mechanism(s) of its antitumor properties are not fully characterized. In the present study, we evaluated the radiosensitizing effects of the water‑soluble sinomenine, sinomenine hydrochloride (SH) in human cervical cancer cell line (HeLa). SH sensitized HeLa cells to ionizing radiation (IR) by promoting accumulation of IR‑induced DNA double‑strand breaks (DSBs) and also by interfering with DNA damage checkpoint activation. We then investigated the molecular mechanisms underlying the SH‑mediated cellular sensitization to IR and found that SH inhibited the expression of DNA damage response (DDR) factors Ku80 and Rad51 at the transcription level. Finally, the radiosensitizing activity of SH was confirmed in a cervical cancer mouse xenograft model. The combinatorial treatment of SH and IR significantly slowed the tumor growth rate compared with IR alone. Collectively, our study not only provides molecular insights into the novel role of SH in cellular response to IR, but also suggests a therapeutic potential of SH as a radiosensitizer in cervical cancer therapy.

Topics: Animals; Cell Cycle Checkpoints; DNA Breaks, Double-Stranded; DNA Damage; Female; HeLa Cells; Humans; Mice; Morphinans; Radiation Tolerance; Radiation-Sensitizing Agents; Radiation, Ionizing; Sinomenium; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays