CN-117717547-B - Application of harmine in CCNE1 amplified ovarian cancer

Abstract

The invention relates to an application of harmine in preparing a medicine for treating CCNE1 amplified ovarian cancer. The CCNE1 amplified ovarian cancer cell line is selected from SKOV3 cell line, HEY cell line, a2780 cell line, OVCAR8 cell line, or OVCAR3 cell line. The invention discovers that Harmine has obvious specific toxicity to ovarian cancer cells amplified by CCNE1 through researches. Cell experiments show that Harmine has a significantly lower IC50 value in ovarian cancer cells with high expression of CCNE1 than in ovarian cancer cells with low expression of CCNE 1. Therefore, haimine can specifically kill the ovarian cancer cells amplified by the CCNE1, and is expected to become an accurate therapeutic drug for the ovarian cancer amplified by the CCNE 1.

Inventors

• WANG YU
• XUE RENHAO
• ZHANG HAO

Assignees

• 上海市第一妇婴保健院

Dates

Publication Date

20260508

Application Date

20240125

Claims (2)

1. 1. The application of harmine in preparing medicines for treating CCNE1 amplified ovarian cancer is provided.
2. 2. The use according to claim 1, wherein the CCNE 1-amplified ovarian cancer cell line is selected from SKOV3, HEY, a2780, OVCAR8 or OVCAR3 cell lines.

Description

Application of harmine in CCNE1 amplified ovarian cancer Technical Field The invention relates to the technical field of medicines, in particular to an application of harmine in preparing a medicine for treating CCNE1 amplified ovarian cancer. Background The profile of CCNE1 amplified ovarian cancer and the current state of drug development are that ovarian cancer is the gynecological malignant tumor [1] with the highest mortality rate. The latest data show that 19710 new cases and 13270 death cases [2] are present every year worldwide. Currently, the preferred treatment modality for ovarian cancer is surgery in combination with platinum-based chemotherapy [3], but the overall 5-year survival rate is only 30-50% [4]. The phenomenon of CCNE1 gene amplification has been reported [5] in various malignant tumors, with a more high incidence of about 20% [6-8] in ovarian cancer. The CCNE1 gene encodes cyclin E1 (cyclin E1), responsible for regulating the transition of the cell cycle from G1 phase to S phase, thus bringing the cell into the DNA synthesis phase (i.e., S phase) [9]. Under normal conditions, cyclin E1 protein levels are tightly regulated [10]. CCNE1 amplification results in an abnormal increase [5] in cyclin E1 protein levels, leading to G1-S cell cycle checkpoint abrogation and an acceleration [11] in cell cycle progression, allowing uncontrolled division of tumor cells. Thus, CCNE 1-amplified ovarian cancer tends to be highly malignant. Meanwhile, CCNE1 amplification has been reported to be associated with drug resistance of standard platinum-taxane chemotherapy [8,12] and PARP inhibitor resistance [13], which make CCNE1 amplified ovarian cancer a recognized refractory ovarian cancer. At present, no effective targeted therapy is available, and no medicine for accurately treating CCNE1 amplified ovarian cancer is available. At present, few specific drug molecules aiming at CCNE1 amplified ovarian cancer enter clinical experiments, but the results are not ideal. Only one phase II clinical trial has been completed to date, namely, treatment of advanced and recurrent malignant solid tumors (NCT 03253679) of CCNE 1-amplified type including ovarian cancer with a single drug of WEE1 inhibitor Adavosertib (AZD 1775), although the results were valid, the study sample size was small and some patients required additional drug anti-emetic treatment [14] at the drug dose given by the study regimen. Currently, another phase II clinical trial for the single treatment of CCNE 1-highly expressed advanced serous ovarian cancer with AZD1775 is ongoing (ACTRN 12619001185156). Meanwhile, phase I clinical trials of two CDK2 inhibitors are currently underway, one being BLU-222 single and combination therapy (NCT 05252416) and the other being INX-315 single therapy (NCT 05735080), however, given the apparent off-target effects of CDK2 inhibitors, their clinical prospects are not optimistic [15]. In addition, recent PKMYT inhibitor RP-6306 alone and in combination with ATR inhibitor RP-3500 for treatment of CCNE 1-amplified solid tumors [16] have also entered phase I clinical trials (EUCTR 2021-001637-39-DK). In summary, CCNE 1-amplified ovarian cancer is a hotspot in current drug development, but no ideal solution has been found to date. According to the current situation of application of harmine (Harmine) as a medicine molecule, according to the current research on the amplified ovarian cancer of the CCNE1, the inhibition of homologous recombination repair of DNA damage or the blocking of G2-M phase conversion of cell cycle can possibly form specific cytotoxicity on the amplified ovarian cancer cells of the CCNE 1. Therefore, to find an effective drug treatment scheme for CCNE1 amplified ovarian cancer, novel drug molecules can be found according to the above mechanism, namely, effective molecules for selectively killing CCNE1 amplified ovarian cancer cells are found from the existing homologous recombination repair inhibitors and G2/M blockers. Researches report that harmine (harmine, 7-methoxy-1-methyl-9H-pyrido [3,4-b ] indole) is a natural product molecule with the functions of inhibiting homologous recombination and repairing [17,18] and G2/M cell cycle blocking [18][19], and has potential to be an accurate drug for specifically treating CCNE1 amplified ovarian cancer. Harmine is a natural alkaloid with broad-spectrum anti-inflammatory and anti-tumor activity. Harmine was originally isolated from the seed of the medicinal plant peganum harmala, which grows in the middle east and in some arid areas of china, and has long been widely used [20] in folk medicine for its anti-inflammatory effect. In addition, harmine is also a broad-spectrum antitumor agent, and its antitumor effect has been reported [21-25] in various malignant tumors including ovarian cancer. Currently harmine and its derivatives are used as broad-spectrum antitumor agents to inhibit various tumors including ovarian cancer, and various patents have be