Abstract
The anti-tumor effect of a chelating phen-based ligand 2,9-di-sec-butyl-1,10-phenanthroline (dsBPT) and its combination with cisplatin were examined in both lung and head and neck cancer cell lines and xenograft animal models in this study. The effects of this agent on cell cycle and apoptosis were investigated. Protein markers relevant to these mechanisms were also assessed. We found that the inhibitory effect of dsBPT on lung and head and neck cancer cell growth (IC50 ranged between 0.1–0.2 μM) was 10 times greater than that on normal epithelial cells. dsBPT alone induced autophagy, G1 cell cycle arrest, and apoptosis. Our in vivo studies indicated that dsBPT inhibited tumor growth in a dose-dependent manner in a head and neck cancer xenograft mouse model. The combination of dsBPT with cisplatin synergistically inhibited cancer cell growth with a combination index of 0.3. Moreover, the combination significantly reduced tumor volume as compared with the untreated control (p = 0.0017) in a head and neck cancer xenograft model. No organ related toxicities were observed in treated animals. Our data suggest that dsBPT is a novel and potent antitumor drug that warrants further preclinical and clinical development either as a single agent or in combination with known chemotherapy drugs such as cisplatin.
Highlights
Cisplatin has been widely used over the past 30 years to successfully treat a variety of cancers, including testicular, ovarian, head and neck, and bladder cancers [1,2,3,4]
It was found that dsBPT had IC50 values ranging from 50–200 nM in these lung cancer and head and neck squamous cancer cell lines (HNSCC) cell lines (Fig 1B), representing a 20–100–fold higher efficacy than cisplatin (Fig 1C). dsBPT and cisplatin were used to treat an immortalized non-tumorigenic bronchial epithelial cell line (BEAS-2B). dsBPT inhibited growth of this cell line at higher concentrations than the cancer cell lines with IC50 around 1.5 μM (Fig 1D)
It was noted that the IC50 of dsBPT was over 100 times lower than that of cisplatin for the H1703 cancer cell line which is insensitive to cisplatin
Summary
Cisplatin has been widely used over the past 30 years to successfully treat a variety of cancers, including testicular, ovarian, head and neck, and bladder cancers [1,2,3,4]. Augmenting our recent report in which this compound was tested for activity against glioblastoma tumor [16], the work reported here describes testing of this compound against head and neck and lung tumor cell lines and reports the first data in regard to a combined therapy regime with this agent providing new insight into the potential antitumor mechanism of dsBPT. Cell viability assays revealed that dsBPT possessed significant anti-proliferation activity against head and neck and lung cancer cell lines, including one tumor cell line that has been previously shown to be resistant to cisplatin. These results prompted the investigation of the antitumor properties of dsBPT against mouse xenograft tumors generated from two of the cancer cell lines. The results of the assessment of the in vivo antitumor activity of dsBPT, the in vivo antitumor activity of the dsBPT-cisplatin combination therapy, and the potential tumor cell death pathways initiated by this compound are described
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