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Synergistic antitumor activity of pro‐apoptotic agent PAC‐1 with cisplatinum by the activation of CASP3 in pulmonary adenocarcinoma cell line H1299
Author(s) -
Huang Jianqing,
Liang Hongling,
Zhang Xuchao,
Xie Zhi,
Jin Tianen
Publication year - 2016
Publication title -
asia‐pacific journal of clinical oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.73
H-Index - 29
eISSN - 1743-7563
pISSN - 1743-7555
DOI - 10.1111/ajco.12419
Subject(s) - apoptosis , chemistry , pulmonary adenocarcinoma , adenocarcinoma , pharmacology , medicine , cancer , biochemistry
Aim Evasion of apoptosis is a hallmark of human cancer cells. We sought to explore the potential synergistic antitumor activity and underlying mechanisms of the pro‐apoptotic agent PAC‐1 plus cisplatinum (Cis) in non‐small cell lung cancer ( NSCLC ) cell lines. Methods The adenocarcinoma cell lines H1299, A549, PC9, H1650 and H1975 were used as in vitro models. Colorimetric MTT assays, Western blotting and flow cytometry were used to evaluate the anti‐growth effects of PAC‐1 and/or Cis and apoptosis status. The activated form of CASP3 ( C‐CASP3 ) was assessed by immunofluorescent staining. Results Single‐agent Cis and PAC‐1 were able to inhibit the cancer cell growth in certain dose ranges, with IC 50 values of 1.9–11.7 and 5.6–14.8 μM, respectively. Sequential Cis→ PAC‐1 or concurrent Cis + PAC‐1 , but not PAC‐1 →Cis combinations showed synergistic effects on cell growth inhibition in H1299 cells (combination index, CI ≤ 0.6). In contrast, other combination modes mostly showed seemingly antagonistic effects (CI > 1.0). Flow cytometric analysis showed that Cis→ PAC‐1 sequential combination showed strong pro‐apoptotic effects in H1299 cells. Western blots showed that in H1299, PC9 and H1975 cells, PAC‐1 promoted the C‐CASP3 , but only in H1299 cells was there a synergistic effect with Cis on the CASP3 activation. Conclusions PAC‐1 showed anti‐tumor activity in NSCLCs in vitro and a synergistic effect with cisplatin in EGFR wt KRAS w t H1299 cells. Our data suggest a potential treatment approach using cisplatin plus a pro‐apoptotic agent acting via CASP3 activation for this subgroup of pulmonary adenocarcinomas.