Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549

Abstract

Nonsmall cell lung cancer (NSCLC) represents an important cause of mortality worldwide due to its aggressiveness and growing resistance to currently available therapy. Cucurbitacins have emerged as novel potential anticancer agents showing strong antiproliferative effects and can be promising candidates for combined treatments with clinically used anticancer agents. This study investigates the synergistic antiproliferative effects of a new semisynthetic derivative of cucurbitacin B (DACE) with three chemotherapy drugs: cisplatin (CIS), irinotecan (IRI), and paclitaxel (PAC) on A549 cells. The most effective combinations were selected for studies of the mechanism of action. Using an in silico tool, DACE seems to act by a different mechanism of action when compared with that of different classes of drugs already used in clinical settings. DACE also showed potent synergic effects with drugs, and the most potent combinations induced G2/M cell cycle arrest by modulating survivin and p53 expression, disruption of F-actin cytoskeleton, and cell death by apoptosis. These treatments completely inhibited the clonogenic potential and did not reduce the proliferation of nontumoral lung cells (MRC-5). DACE also showed relevant antimigratory and anti-invasive effects, and combined treatments modulated cell migration signaling pathways evolved with metastasis progression. The effects of DACE associated with drugs was potentiated by the oxidant agent l-buthionine-sulfoximine (BSO), and attenuated by N-acetilcysteine (NAC), an antioxidant agent. The antiproliferative effects induced by combined treatments were attenuated by a pan-caspase inhibitor, indicating that the effects of these treatments are dependent on caspase activity. Our data highlight the therapeutic potential of DACE used in combination with known chemotherapy drugs and offer important insights for the development of more effective and selective therapies against lung cancer.

Cucurbitacin B inhibits the migration and invasion of breast cancer cells by altering the biomechanical properties of cells

“…F‐actin and vimentin are also major mediators that regulate the cytoskeletal network tension (Janmey, Euteneuer, Traub, & Schliwa, ; Liu, Lin, Tang, & Wang, ). A previous study reported that CuB caused morphological changes in the cytoskeleton of lung cancer cells by inducing F‐actin polymerization (Marostica et al, ). Our data demonstrate that increasing the CuB treatment concentration, F‐actin aggregates around the nucleus.…”

Cucurbitacin B induces autophagy and apoptosis by suppressing CIP2A/PP2A/mTORC1 signaling axis in human cisplatin resistant gastric cancer cells

“…CuB is a representative natural compound for anticancer activities. Recently, CuB was reported to enhance the anticancer effects of DDP in lung, ovarian, cutaneous squamous cell carcinoma, and laryngeal squamous cell carcinoma (20,(36)(37)(38). However, the relationship between CuB and DDP-resistance in GC cells has yet to be firmly established.…”

Synergistic Anti-proliferative Effects of Cucurbitacin I and Irinotecan on Human Colorectal Cancer Cell Lines

“…Moreover, some drug combinations show strong synergism that helps to achieve the same therapeutic effect with lower dose and, hence, less toxicity [34][35][36][37][38][39][40][41][42]. Some reports have shown that cucurbitacins show a synergistic effect with chemotherapeutic agents that are already established in the treatment of human cancers [38][39][40][41][42].…”