PNAS-4, a novel pro-apoptotic gene, can potentiate antineoplastic effects of cisplatin
Zhu Yuan1, Fei Yan, Yong-sheng Wang
1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, 1# Keyuan Road 4, Gaopeng Street, High Technological Development Zone 610041, Chengdu, China.
Purpose:
PNAS-4, a novel pro-apoptotic gene activated during the early response to DNA damage, can inhibit proliferation via apoptosis when overexpressed in some tumor cells. The objectives of this study were to determine whether PNAS-4 could enhance apoptosis induced by cisplatin besides its induction of apoptosis, and to evaluate the usefulness of combined treatment with mouse PNAS-4 (mPNAS-4) gene therapy and low-dose cisplatin chemotherapy in the inhibition of tumor growth in colon carcinoma (CT26) and Lewis lung carcinoma (LL/2) murine models.
Methods:
In this study, the in vitro growth-inhibitory and pro-apoptotic effects of PNAS-4 and/or cisplatin on CT26, LL/2, and SKOV3 cancer cells were assessed by MTT assay, flow cytometric analysis, DNA fragmentation, and morphological analysis, respectively. The in vivo antitumor activity of combined treatment with mPNAS-4 gene therapy and low-dose cisplatin were evaluated in the inhibition of tumor growth in colon carcinoma (CT26) and Lewis lung carcinoma (LL/2) murine models. Tumor volume and survival time were observed. Induction of apoptosis was also assessed in tumor tissues.
Results:
In vitro, PNAS-4 inhibited proliferation of colon carcinoma (CT26), Lewis lung carcinoma (LL/2) and human ovarian cancer (SKOV3) cell lines via apoptosis, and significantly enhanced the apoptosis of CT26, LL/2, and SKOV3 cells induced by cisplatin. In vivo systemic administration of expression plasmid encoding mPNAS-4 (pcDNA3.1-mPS) and cisplatin, significantly decreased tumor growth through increased tumor cell apoptosis compared to treatment with mPNAS-4 or cisplatin alone.
Conclusions:
Our data suggests that the combined treatment with mPNAS-4 plus cisplatin may augment the induction of apoptosis in tumor cells in vitro and in vivo, and that the augmented antitumor activity in vivo may result from the increased induction of apoptosis. The present study may provide a novel way to augment the antitumor efficacy of cytotoxic chemotherapy.
Insights
This study shows that combining mouse PNAS-4 (mPNAS-4) gene therapy with cisplatin chemotherapy effectively inhibits tumor growth. The combination therapy enhances apoptosis in cancer cells, offering a novel approach to improve chemotherapy efficacy.
Area of Science:
- Molecular biology
- Cancer research
- Gene therapy
Background:
- PNAS-4 is a pro-apoptotic gene that inhibits tumor cell proliferation.
- Overexpression of PNAS-4 can induce apoptosis in certain cancer cells.
Purpose of the Study:
- To determine if PNAS-4 enhances cisplatin-induced apoptosis.
- To evaluate the efficacy of combined mPNAS-4 gene therapy and low-dose cisplatin in inhibiting colon and lung carcinoma growth in murine models.
Main Methods:
- In vitro assessment of PNAS-4 and cisplatin effects on cancer cell lines (CT26, LL/2, SKOV3) using MTT assay, flow cytometry, DNA fragmentation, and morphological analysis.
- In vivo evaluation of combined mPNAS-4 gene therapy and cisplatin in CT26 and LL/2 murine models, monitoring tumor volume, survival, and apoptosis induction in tumor tissues.
Main Results:
- PNAS-4 inhibited proliferation and enhanced cisplatin-induced apoptosis in CT26, LL/2, and SKOV3 cell lines in vitro.
- Combined systemic administration of mPNAS-4 and cisplatin significantly reduced tumor growth in vivo by increasing tumor cell apoptosis compared to monotherapy.
Conclusions:
- Combined mPNAS-4 and cisplatin treatment augments apoptosis in tumor cells both in vitro and in vivo.
- The enhanced antitumor activity observed in vivo is likely due to increased apoptosis induction.
- This combined approach offers a novel strategy to enhance the efficacy of cytotoxic chemotherapy.
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