Chemosensitizing effects of crebanine and its analogues in human drug resistance ovarian cancer cells

ผลการเพิ่มความไวต่อยาเคมีบำบัดของครีบานีนและแอนะล็อกในเซลล์มะเร็งรังไข่มนุษย์ที่ดื้อยา

Name: May Thuu Mon

ThaSH: Chemotherapy

Classification :.DDC: 615.58

ThaSH: Cancer -- Chemotherapy

Abstract: Ovarian cancer is one of the foremost causes of death from gynecologic malignancies worldwide. The standard treatment for advanced ovarian cancer is combination chemotherapy of paclitaxel plus a platinum compound (carboplatin or cisplatin). The main cytotoxic activity of platinum compound is the formation of DNA adducts mainly intra-stranded crosslinks, thus triggering several signal transduction pathways leading to apoptosis. Although platinum based chemotherapy is an effective treatment for majority of ovarian cancer patients, platinum drug resistance and side effects are the major limitation of current therapeutic concepts. Up to date, natural products as chemosensitizers that enhance drug sensitivity and improve antineoplastic effects have been investigated. Using of natural products as adjuvant therapy would be promising way for therapeutic and preventive remedies for drug resistance. Several studies proposed the anti-invasive and anti-proliferative effects of aporphine alkaloids such as crebanine isolated from Stephania venosa in human cancer cell lines. Nevertheless, chemosensitizing effect of crebanine and its analogues from S. venosa have not been investigated. Therefore, our study dedicated to determine the effect of crebanine, O-methylbulbocapnine, tetrahydropalmatine, and N-methyl tetrahydropalmatine on human drug resistance ovarian cancer cells. In the present study, crebanine and O-methylbulbocapnine enhanced cisplatin sensitivity in intrinsic cisplatin resistant SKOV3 cells, but not in wild type A2780 cells and its acquired resistance type A2780/cis. Tetrahydropalmatine and N-methyl tetrahydropalmatine, had no synergistic effect on cisplatin sensitivity in all three cell lines. Chemosensitizing effects of crebanine and O-methylbulbocapnine in SKOV3 cells were mediated via activating apoptosis-induced cell death through caspase-3, -8 and cleaved PARP and via inhibiting survival and anti-apoptotic protein expressions, including survivin, cIAP-2, Bcl-xL and IL-6. Cisplatin induced Akt and NF-κB signaling pathways, but not MAPK, AP-1 and STAT3 in SKOV3 cells. We also confirmed that pharmacological inhibition of Akt activity by its selective inhibitor (LY294002) leads to increased platinum sensitivity in intrinsic cisplatin resistance SKOV3 cells. Therefore, the data suggest that Akt/ NF-κB pathway plays a role in platinum resistance in ovarian cancer. In the present study, crebanine and O-methylbulbocapnine can also inhibit Akt/NF-κB signaling, favouring cisplatin sensitivity. Tumor cells synthesize and secrete various chemokines and growth factors which can act in autocrine or paracrine manner in stimulation of tumor cell proliferation and drug resistance. IL6 appears to be one of the important tumor promoting factors in ovarian carcinoma, particularly in the setting of tumor progression and drug resistance. Our results showed that crebanine could reduce IL-6 mediated augmentation of STAT3 protein phosphorylation and its downstream signaling proteins concerned with tumor cell survival and invasion in SKOV3 cells. In order to determine the relationship between IL-6 production and the responses to chemotherapy in clinical settings, the primary cancer cell culture method was established by using the tumor tissue of ovarian carcinoma patients. According to the follow up data after performing platinum-based chemotherapy on ten ovarian cancer patients, seven (70%) patients presented a complete or partial response to chemotherapy, and three (30%) patients showed progression and resistance to platinum-based chemotherapy. Among 3 nonresponsive patients, carboplatin-induced IL-6 production was found in 2 patients whereas IL-6 level upon exposure to carboplatin in ex-vivo studies did not change obviously in all responsive patients. Therefore, the data indicated that carboplatin-induced IL-6 production had a significant association with a poor clinical response to chemotherapy (p=0.016). Moreover, treatment of crebanine to primary cell culture with high IL-6 production (more than two fold) in response to carboplatin resulted in increased sensitivity to platinum drug. In conclusion, crebanine obtained from S. venosa would be an effective adjuvant agent to sensitize the platinum-based chemotherapeutic drugs and to decrease the IL-6 induced ovarian cancer aggressiveness

Chiang Mai University Library

Address: Chiang Mai

Email: cmulibref@cmu.ac.th

Name: Chichamai Ovatlarnporn

Role: Chairman

Name: Pornngarm Dejkriengkraikul

Role: Member

Name: Ratana Banjerdpongchai

Role: Member

Name: Supachai Yodkeeree

Role: Member

Name: Pornsiri Pitchakarn

Role: Member

Created: 2018

Modified: 2020-01-04

Issued: 2020-01-04

วิทยานิพนธ์/Thesis

application/pdf

CallNumber: Th 615.58 M467C 2018

eng

DegreeName: Doctor of Philosophy

Level: Doctoral Degree

Descipline: Biochemistry

Grantor: Chiang Mai University

©copyrights Chiang Mai University

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