Pharmacological modulation of autophagy enhances Newcastle disease virus-mediated oncolysis in drug-resistant lung cancer cells

Abstract

BackgroundOncolytic viruses represent a promising therapy against cancers with acquired drug resistance. However, low efficacy limits its clinical application. The objective of this study is to investigate whether pharmacologically modulating autophagy could enhance oncolytic Newcastle disease virus (NDV) strain NDV/FMW virotherapy of drug-resistant lung cancer cells.MethodsThe effect of NDV/FMW infection on autophagy machinery in A549 lung cancer cell lines resistant to cisplatin (A549/DDP) or paclitaxel (A549/PTX) was investigated by detection of GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta, formation of double-membrane vesicles and conversion of the nonlipidated form of LC3 (LC3-I) to the phosphatidylethanolamine-conjugated form (LC3-II). The effects of autophagy inhibitor chloroquine (CQ) and autophagy inducer rapamycin on NDV/FMW-mediated antitumor activity were evaluated both in culture cells and in mice bearing drug-resistant lung cancer cells.ResultsWe show that NDV/FMW triggers autophagy in A549/PTX cells via dampening the class I PI3K/Akt/mTOR/p70S6K pathway, which inhibits autophagy. On the contrary, NDV/FMW infection attenuates the autophagic process in A549/DDP cells through the activation of the negative regulatory pathway. Furthermore, combination with CQ or knockdown of ATG5 significantly enhances NDV/FMW-mediated antitumor effects on A549/DDP cells, while the oncolytic efficacy of NDV/FMW in A549/PTX cells is significantly improved by rapamycin. Interestingly, autophagy modulation does not increase virus progeny in these drug resistant cells. Importantly, CQ or rapamycin significantly potentiates NDV/FMW oncolytic activity in mice bearing A549/DDP or A549/PTX cells respectively.ConclusionsThese results demonstrate that combination treatment with autophagy modulators is an effective strategy to augment the therapeutic activity of NDV/FMW against drug-resistant lung cancers.

Inactivated Sendai virus induces apoptosis and autophagy via the PI3K/Akt/mTOR/p70S6K pathway in human non-small cell lung cancer cells

“…The increased HVJ-E-mediated apoptosis in the presence of autophagy modulators was further verified by enhanced caspase-3 and PARP cleavage. Interestingly, Jiang et al recently reported that neither CQ nor rapamycin could augment the anticancer effects of NDV in A549 cells, which differs from the current results [3]. Therefore, it is possible that the decision whether to use autophagy inducers or inhibitors in combination virotherapy should be virus strain-and cancer cell line-dependent.…”

“…This effect was caused by inhibition of the class I PI3K/Akt/ mTOR/p70S6K pathway, which negatively regulates autophagy [22]. Previous studies reported that cisplatin treatment induces autophagy in A549 cells, and the acquired cisplatin resistance in A549 cells is associated with enhanced autophagy, suggesting that autophagy may act as a survival mechanism in cisplatin-resistant A549 lung cancer cells [3,23]. Having documented that HVJ-E induces both apoptosis and autophagy in A549 and A549/DDP cells, we next investigated the role that autophagy plays in apoptosis.…”

“…Cisplatin (DDP) is used widely as an effective antitumor agent for the treatment of various types of malignant cancers [2]. However, acquired drug resistance against first-line chemotherapeutics, such as DDP, is a major contributing factor to chemotherapy failure in non-small cell lung cancer (NSCLC) patients [3]. Therefore, it is urgent to find novel anti-tumor agents with few side effects to meet the unmet therapeutic needs of NSCLC patients.…”

Synergistic increase in efficacy of a combination of 2-deoxy-d-glucose and cisplatin in normoxia and hypoxia: switch from autophagy to apoptosis

“…It is therefore possible that perifosine and MK-2206, the AKT inhibitors already being used for gliomas, could be combined with 2-DG to produce a synergistic effect and to reverse the effect of autophagy to apoptosis. In a recent study by Jiang et al [33], it was shown that autophagic modulators like rapamycin and CQ can enhance the in vitro and in vivo oncolytic effects of Newcastle disease virus-mediated oncolysis in drug-resistant lung cancer cell lines. Autophagic inhibitors along with the conventional chemotherapy can thus prove to be rational combinations for reducing chemoresistance in different cancers.…”

Antitumor and immunostimulatory activities of a genotype V recombinant attenuated veterinary Newcastle disease virus vaccine

“…Keeping this in mind, our next aim characterizing rNDV-P05 was to explore whether the virus had the capability or not to induce apoptosis over a panel of tumor cell lines from a variety of tissues. In this study, we have demonstrated that rNDV-P05 was able to induce apoptosis over four from five tested cell lines, which had previously shown susceptibility to NDV (29)(30)(31)(32). In solid tumors, this is important for virotherapy, given that the cell death induced by the virus in the tumor microenvironment can evoke not only local, but also a systemic tumor-specific immune surveillance against primary and metastatic malignant cells.…”