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The cancer stemness inhibitor napabucasin suppresses small cell lung cancer growth through SOX2 expression
Jhy-Ming Li1,2, Ping-Chih Hsu3, Feng-Che Kuan4
1Department of Animal Science, National Chiayi University Chiayi, Taiwan.
Abstract:
Small cell lung cancer (SCLC) is a high-grade malignancy of neuroendocrine origin characterized by aggressive cell growth and a poor survival rate of patients. Currently, the treatment options for SCLC remain limited despite platinum-based chemotherapy. Systemic chemotherapy is effective for SCLC, but most patients eventually acquire drug resistance, which leads to treatment failure. Stemness-high cancer cells show characteristics of advanced tumorigenesis and metastasis and have high potential in promoting treatment resistance and disease relapse. Napabucasin (BBI608), a novel small-molecule drug targeting on signal transducer and activator of transcription 3 (STAT3), was shown to suppress the progression and metastasis of stemness-high cancer stem cells in various cancers. Here, we demonstrated that napabucasin significantly decreased viability and colony formation and induced the arrest of S-phase cell cycle and apoptosis in cisplatin-resistant SCLC cells. Findings from mechanistic studies further indicated that napabucasin directly downregulated the expression of SOX2 in cisplatin-resistant SCLC cells; however, dysfunctional SOX2 expression in SCLC cells was associated with interference in the napabucasin-mediated reduction of cell viability. In contrast, napabucasin-induced viability reduction was restored in these cells when SOX2 expression was upregulated. Furthermore, napabucasin significantly inhibited cisplatin-resistant SCLC cell xenograft growth in vivo by downregulating SOX2 and inducing apoptosis. These data demonstrate that napabucasin may be a novel drug for the clinical treatment of cisplatin-resistant SCLC.
Insights
Napabucasin effectively combats cisplatin-resistant small cell lung cancer (SCLC) by targeting stemness and downregulating SOX2. This novel drug shows promise in inhibiting tumor growth and inducing apoptosis, offering a potential new treatment for SCLC.
Area of Science:
- Oncology
- Cancer Therapeutics
- Molecular Biology
Background:
- Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with limited treatment options.
- Chemotherapy resistance and cancer stem cell (CSC) properties contribute to SCLC relapse and poor patient outcomes.
- Signal transducer and activator of transcription 3 (STAT3) signaling is implicated in CSC progression and treatment resistance.
Purpose of the Study:
- To investigate the efficacy of napabucasin, a STAT3 inhibitor, against cisplatin-resistant SCLC.
- To elucidate the mechanisms by which napabucasin affects CSC properties and tumor growth in SCLC.
- To evaluate the therapeutic potential of napabucasin in preclinical models of SCLC.
Main Methods:
- Napabucasin treatment of cisplatin-resistant SCLC cell lines.
- Assessment of cell viability, colony formation, cell cycle progression, and apoptosis.
- Analysis of SOX2 expression and its role in napabucasin's efficacy.
- Evaluation of napabucasin's effect on SCLC xenograft growth in vivo.
Main Results:
- Napabucasin significantly reduced viability and colony formation in cisplatin-resistant SCLC cells.
- Napabucasin induced S-phase cell cycle arrest and apoptosis.
- Napabucasin downregulated SOX2 expression, which was crucial for its anti-proliferative effects.
- Napabucasin inhibited tumor growth in SCLC xenografts by downregulating SOX2 and promoting apoptosis.
Conclusions:
- Napabucasin demonstrates significant anti-cancer activity against cisplatin-resistant SCLC.
- Targeting STAT3 and SOX2 with napabucasin represents a promising therapeutic strategy for SCLC.
- Napabucasin holds potential as a novel clinical treatment for patients with drug-resistant SCLC.
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