Abstract A51: Antineoplastic activity of novel synthetic compound pterocarpanquinone LQB-118 in lung cancer cells
Authors: Silva Karina Lani , Souza Paloma Silva de , Costa Paulo R.R. , Maia Raquel Ciuvalschi 
Published: May 2015

Introduction and objectives: Lung cancer is a significant health concern in many countries as it is the leading cause of cancer-related mortality worldwide. Although significant advances have been made in the treatment of this disease, either traditional chemotherapy or target agents fail to provide long-term benefits for the majority of patients. Intrinsic or acquired drug resistance is a major cause of failure in the treatment of lung cancer and remains an unsolved pharmacological problem. Therefore, the development of new therapies is needed to improve overall survival of these patients. The pterocarpanquinone LQB-118, a molecular hybrid structurally related to lapachol has emerged as a possible cytotoxic molecule for cancer cells by our group. This compound showed to be cytotoxic against leukemic cells regardless their multidrug resistance profiles while low toxicity was observed against normal peripheral blood mononucleated cells (PBMC). LQB-118 has already been patented in Brazil at National Institute of Industry Propriety under the code 020080139198. Although, cytotoxic effect of LQB-118 has been demonstrated in some tumor cells, the pathway through which this compound induces cell death remains unknown in lung cancer cells. Hence, in the present work, we analyzed the cell death process induced by LQB-118 in non-small cell lung cancer (NSCLC) cell line A549.

Materials and Methods: Cisplatin, is one of the most commonly used chemotherapeutic agent in the treatment of NSCLC and was used as comparision to LQB-118 effects. For this purpose we carried out a cell viability assay by MTT and a clonogenic survival assay by crystal violet. To study apoptosis induction by compounds the annexin-V/propidium iodide (PI) label, sub-G0 content/cell cycle profile and activation of caspase-3 were examined by FACS analysis. Western blot was performed to evaluate the capability of LQB-118 in changing the expression of some proteins involved in proliferative and antiapoptotic pathways signaling.

Results: We found that LQB-118 and cisplatin reduced cell viability in approximately 50% of cells at the concentration of 5μM after 48h of exposure and inhibited drastically colony formation. This cell viability reduction caused by LQB-118 was accompanied by an increase in the percentage of annexin-V/PI staining cells (around 30%) similar as observed for cisplatin. Activation of caspase-3 (around 25%) at 48h was also observed after LQB-118 exposure. However, the percentage of caspase-3 positive cells was higher after cisplatin treatment (around 60%). The new compound was also capable of inducing an arrest in G2/M cell cycle phase, however it was more pronounced in cisplatin treated cells. Interestingly, LQB-118 decreased significantly the expression of XIAP and survivin proteins, members of inhibitor of apoptosis proteins, responsible for drug resistance in several tumors. The inhibition of XIAP and survivin expression by LQB-118 was stronger than that observed for cisplatin treatment at 24h of culture. Analysis of epidermal growth factor receptor (EGFR) expression and proteins involved in signaling pathways downstream EGFR such as extracellular signal-regulated kinases 1/2 (ERK1/2) and Akt was also evaluated. No changes in EGFR expression or ERK1/2 phosphorilation were observed. Nevertheless, an inhibition of phosphorilated Akt was showed after LQB-118 treatment, suggesting that this compound acts inducing apoptosis through PI3Kinase pathway inhibition.

Conclusion: Our results suggest LQB-118 as a potential drug for NSCLC treatment once their effects in A549 cell line were similar that observed for cisplatin, with the advantage that LQB-118 seems to be less toxic than cisplatin in PBMC cells. Further studies are necessary to elucidate the mechanisms of action of this compound.

Financial support: INCT, FAPERJ, CNPq and Programa de Oncobiologia.

Citation Format: Karina Lani Silva, Paloma Silva de Souza, Paulo R.R. Costa, Raquel Ciuvalschi Maia. Antineoplastic activity of novel synthetic compound pterocarpanquinone LQB-118 in lung cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A51.