Cisplatin Synergistically Enhances Antitumor Potency of Conditionally Replicating Adenovirus via p53 Dependent or Independent Pathways in Human Lung Carcinoma.

Sakhawat Ali,Yinghui Huang,Ma Ling,Aamir Khan,Muhammad Tahir,Xue Chen

doi:10.3390/ijms20051125

Abstract

Cisplatin is ranked as one of the most powerful and commonly prescribed anti-tumor chemotherapeutic agents which improve survival in many solid tumors including non-small cell lung cancer. However, the treatment of advanced lung cancer is restricted due to chemotherapy resistance. Here, we developed and investigated survivin promoter regulating conditionally replicating adenovirus (CRAd) for its anti-tumor potential alone or in combination with cisplatin in two lung cancer cells, H23, H2126, and their resistant cells, H23/CPR, H2126/CPR. To measure the expression of genes which regulate resistance, adenoviral transduction, metastasis, and apoptosis in cancer cells, RT-PCR and Western blotting were performed. The anti-tumor efficacy of the treatments was evaluated through flow cytometry, MTT and transwell assays. This study demonstrated that co-treatment with cisplatin and CRAd exerts synergistic anti-tumor effects on chemotherapy sensitive lung cancer cells and monotherapy of CRAd could be a practical approach to deal with chemotherapy resistance. Combined treatment induced stronger apoptosis by suppressing the anti-apoptotic molecule Bcl-2, and reversed epithelial to mesenchymal transition. In conclusion, cisplatin synergistically increased the tumor-killing of CRAd by (1) increasing CRAd transduction via enhanced CAR expression and (2) increasing p53 dependent or independent apoptosis of lung cancer cell lines. Also, CRAd alone proved to be a very efficient anti-tumor agent in cancer cells resistant to cisplatin owing to upregulated CAR levels. In an exciting outcome, we have revealed novel therapeutic opportunities to exploit intrinsic and acquired resistance to enhance the therapeutic index of anti-tumor treatment in lung cancer.

Highlights

Lung cancer is accepted as the most prevalent and fatal malignancy worldwide. This is primarily owing to its fast advancement to metastatic stage IV before diagnosis, the non-small cell lung cancer (NSCLC) [1] which accounts for nearly 95% of all lung cancers [2]
Cisplatin synergizes with conditionally replicating adenovirus (CRAd), and in our previous study we demonstrated that cisplatin resistance might play a crucial role in the regulation of Coxsackievirus and adenovirus receptor (CAR) expression
The results showed that cisplatin effectively elicits apoptosis in sensitive cells by increasing the bax: bcl-2 ratio and enhancing expression of caspase-3 and p53

Summary

Introduction

Lung cancer is accepted as the most prevalent and fatal malignancy worldwide. This is primarily owing to its fast advancement to metastatic stage IV before diagnosis, the non-small cell lung cancer (NSCLC) [1] which accounts for nearly 95% of all lung cancers [2]. Ongoing lung cancer treatments face numerous challenges including but not limited to, complexity and variety of lung cancer subtypes, and acquired resistance [3]. This highlights the significance of searching novel therapeutic strategies which can alleviate the current problems faced by clinicians and culminate in the development of effective and long-lasting individual or combined targeted anti-cancer warheads. The mechanisms underlying the cells resistance to platinum drugs are not fully understood, and their understanding may provide clues for therapeutic strategies to enhance the efficacy of chemotherapy drugs in advanced lung cancer or other malignancies

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