Combination Therapy of Chloroquine and C2-Ceramide Enhances Cytotoxicity in Lung Cancer H460 and H1299 Cells

Chou, Han-Lin; Lin, Yi‐Hsiung; Liu, Wangta; Wu, Chang‐Yi; Li, Ruei‐Nian; Huang, Hurng‐Wern; Chou, Chi‐Hsien; Chiou, Shean‐Jaw; Chiu, Chien‐Chih

doi:10.3390/cancers11030370

Cited by 27 publications

(25 citation statements)

References 32 publications

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“…Based on this knowledge, in vivo studies have started to employ autophagy inhibitors, such as inhibitors of the lysosomal protease and anti-malaric drugs, Chloroquine (CQ) or Hydroxichloroquine (HCQ), to treat cancer, more often in combination with chemotherapies able to induce autophagy [17–19]. Such combinations, mainly used to treat cancer in xenograft mouse models, have registered some successes in controlling tumor growth and prolonging host survival [20–22]. However, in order to avoid tumor rejection, immune deficient mice have been used for these experiments, thus cutting out the possibility to explore the direct and indirect role of autophagy inhibitors on the cells of the immune system [8].…”

Section: Introductionmentioning

confidence: 99%

Autophagy manipulation as a strategy for efficient anticancer therapies: possible consequences

Cirone

Montani

Granato

et al. 2019

J Exp Clin Cancer Res

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Autophagy is a catabolic process whose activation may help cancer cells to adapt to cellular stress although, in some instances, it can induce cell death. Autophagy stimulation or inhibition has been considered an opportunity to treat cancer, especially in combination with anticancer therapies, although autophagy manipulation may be viewed as controversial. Thus, whether to induce or to inhibit autophagy may be the best option in the different cancer patients is still matter of debate. Her we will recapitulate the possible advantages or disadvantages of manipulating autophagy in cancer, not only with the aim to obtain cancer cell death and disable oncogenes, but also to evaluate its interplay with the immune response which is fundamental for the success of anticancer therapies.

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Section: Introductionmentioning

confidence: 99%

Autophagy manipulation as a strategy for efficient anticancer therapies: possible consequences

Cirone

Montani

Granato

et al. 2019

J Exp Clin Cancer Res

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“…Moreover, we also found that xanthohumol potentiates cisplatin apoptotic effects. Although new therapies for the treatment of lung cancer have evolved, NSCLC accounts for 85% of lung cancer cases and more than half of the cases are already metastatic at diagnosis [24]. While the treatment options and approaches for malignant lung cancer have evolved significantly, other factors such as secondary resistance is often associated with poor treatment successes and survival [24][25].…”

Section: Discussionmentioning

confidence: 99%

“…Although new therapies for the treatment of lung cancer have evolved, NSCLC accounts for 85% of lung cancer cases and more than half of the cases are already metastatic at diagnosis [24]. While the treatment options and approaches for malignant lung cancer have evolved significantly, other factors such as secondary resistance is often associated with poor treatment successes and survival [24][25]. Platinum-based chemotherapy including cisplatin in combination with other chemodrugs still remains first line of treatment and has been shown to improve overall survival (OS) in comparison with other drugs such as carboplatin or newer chemodrugs [1,26].…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic Effects of Xanthohumol and Its Combination with Cisplatin on Human Metastatic Lung Cancer H1299 Cells

Long¹,

Parks

Pacurari

et al. 2019

JAMMR

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Aims: Non-small cell lung cancer (NSCLC) accounts for high lung cancer death that is mostly associated with advanced disease stage at diagnosis and resistance to chemotherapy. In the present study, we investigated whether xanthohumol, a prenylated flavonoid of hop plant, induces metastatic lung cancer H1299 cell death, and whether in combination with cisplatin there are additive effects. Methodology: H1299 cells were grown and treated with xanthohumol (6.25, 12.5, or 25 µM), cisplatin (12.5, 25, or 50 µM) and the combination of cisplatin and xanthohumol for 24 h. Cell viability, cell morphology, chromatin condensation, ɣH2AX, cPARP-1, capsase-3, p21WAF1/CIP1 and p14ARF genes were analyzed. Results: Xanthohumol, cisplatin, and the combination of cisplatin and xanthohumol inhibited H1299 cells viability. Cisplatin growth inhibitory effects were potentiated by xanthohumol. Xanthohumol induced chromatin condensation and apoptosis and potentiated cisplatin’s effect vs cisplatin alone. Further investigation of growth inhibitory effects, xanthohumol alone induced γH2AX foci formation and the combination potentiated γH2AX foci formation. Cisplatin, xanthohumol at 25 μM, and the combination of cisplatin and xanthohumol at 6.25 and 12.5 μM increased cPARP-1 level. Active caspase-3 was increased by cisplatin, 12.5 μM of xanthohumol, and the combination of xanthohumol and cisplatin. Xanthohumol at 6.25 or 12.5 μM potentiated cisplatin effect on active caspase-3 and cPARP-1, respectively. Xanthohumol at 25 µM significtly induced the expression cell cycle control genes p21WAF1/CIP1 and p14ARF. These results indicate that xanthohumol inhibits proliferation of H1299 cells and induces cell death through cleavage of PARP-1 and activation of caspase-3. The combination of cisplatin and xanthohumol potentiated cytotoxic effects of each other compound. Conclusion: The present study suggests that xanthohumol poses apoptotic effects and potentiates cisplatin’s growth inhibitory effects on metastatic lung cancer cells.

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“…A study by Chou et al (17) revealed that cotreatment with CQ enhanced the cytotoxicity of C2-ceramide by 2.4-and 3.4-fold respectively compared with single treatment in the two NSCLC cell lines H460 and H1299; moreover, combination treatment significantly reduced the migration and invasion capability of both cell lines. Furthermore, in vivo analysis demonstrated that a combination of C2-ceramide and CQ resulted in a significant tumor-inhibition efficacy in the zebrafish xenograft model compared with single treatment groups, which suggests that the combination was reliable for lung cancer treatment (17). The present study investigated whether the autophagy inhibitor CQ can improve the sensitivity of the A549 lung cancer cell line to EPI, and attempted to elucidate the mechanisms involved.…”

Section: Introductionmentioning

confidence: 98%

“…Chloroquine (CQ) is a commonly used autophagy inhibitor that functions by disrupting the acidic environment of lysosomes and inhibiting the fusion of autophagosomes with lysosomes (16). A study by Chou et al (17) revealed that cotreatment with CQ enhanced the cytotoxicity of C2-ceramide by 2.4-and 3.4-fold respectively compared with single treatment in the two NSCLC cell lines H460 and H1299; moreover, combination treatment significantly reduced the migration and invasion capability of both cell lines. Furthermore, in vivo analysis demonstrated that a combination of C2-ceramide and CQ resulted in a significant tumor-inhibition efficacy in the zebrafish xenograft model compared with single treatment groups, which suggests that the combination was reliable for lung cancer treatment (17).…”

Section: Introductionmentioning

confidence: 99%

Chloroquine increases the anti‑cancer activity of epirubicin in A549 lung cancer cells

Liang

Zhang

et al. 2020

Oncol Lett

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The present study investigated whether the autophagy inhibitor chloroquine (CQ) can improve the sensitivity of the A549 lung cancer cell line to epirubicin (EPI). The Cell Counting Kit 8 (CCK8) assay was used to determine the EPI IC 50 in A549 cells treated for 72 h. A549 cells were treated with Western blot analysis was performed to detect the expression level of the autophagy-associated protein, microtubule associated protein 1 light chain 3 β (LC3B), and apoptosis-associated proteins such as cleaved caspase-9 and cleaved caspase-3. CCK8, colony formation, wound healing and Transwell assays were performed to analyze cell proliferation, migration and invasion capacity. Reverse transcription-quantitative PCR (RT-qPCR) was used to analyze the mRNA expression levels of LC3B and beclin-1, and the apoptosis rate was analyzed by flow cytometry. The IC 50 of EPI was 0.03 µg/ml. The CCK8 results demonstrated that the cell survival rate was lower in CQ + EPI-treated cells when compared with the individual treatment groups. The colony formation results revealed that the number of clones in the EPI + CQ-treated group was reduced compared with EPI or CQ treatment alone. The wound healing assay revealed that migration was reduced in the EPI + CQ-treated group compared with the other treatment groups, and the Transwell results indicated that the number of cells passing through the Matrigel and membrane was lowest in the CQ + EPI treatment group. The mRNA expression levels of LC3B and beclin-1 were increased in the CQ + EPI group by 51.5 and 61.2%, respectively, when compared with the control group. The results indicated that LC3B protein expression was enhanced by EPI in a concentration-dependent manner, and the protein levels of cleaved caspase-3 and cleaved caspase-9 were higher in the combination group than in the EPI alone group. The flow cytometry results demonstrated that the apoptosis rate was highest in the EPI + CQ group. In conclusion, the autophagy inhibitor CQ increased the sensitivity of A549 cells to EPI, and the underlying mechanism of action may be associated with the activation of apoptosis.

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Combination Therapy of Chloroquine and C2-Ceramide Enhances Cytotoxicity in Lung Cancer H460 and H1299 Cells

Cited by 27 publications

References 32 publications

Autophagy manipulation as a strategy for efficient anticancer therapies: possible consequences

Autophagy manipulation as a strategy for efficient anticancer therapies: possible consequences

Cytotoxic Effects of Xanthohumol and Its Combination with Cisplatin on Human Metastatic Lung Cancer H1299 Cells

Chloroquine increases the anti‑cancer activity of epirubicin in A549 lung cancer cells

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