Chloroquine enhances the cytotoxicity of topotecan by inhibiting autophagy in lung cancer cells

Although the anti-malaria drug chloroquine(CQ) has been shown to enhance chemotherapy and radiation sensitivity in clinical trials,the potential mechanisms underlying this enhancement are still unclear.Here,we examined the relevant mechanisms by which the multipotent CQ enhanced the cytotoxicity of topotecan(TPT).The lung cancer cell line A549 was treated with TPT alone or TPT combined with CQ at non-cytotoxic concentrations.Cell viability was assessed using the MTT assay.The percentage of apoptotic cells and the presence of a side population of cells were both determined by flow cytometry.Autophagy and the expression of Bcl-2 family proteins were examined by Western blotting.The accumulation of YFP-LC3 dots and the formation of acidic vesicular organelles were examined by confocal microscopy.CQ sensitized A549 cells to TPT and enhanced TPT-induced apoptosis in a Bcl-2 family protein-independent fashion.CQ inhibited TPT-induced autophagy,which modified the cytotoxicity of TPT.However,CQ failed to modify the transfer of TPT across the cytoplasmic membrane and did not increase lysosomal permeability.This study showed that CQ at non-cytotoxic concentrations potentiated the cytotoxicity of TPT by interfering with autophagy,implying that CQ has significant potential as a chemotherapeutic enhancer.

E2F-1 overexpression inhibits human gastric cancer MGC-803 cell growth in vivo

AIM: To evaluate the influence of E2F-1 on the growth of human gastric cancer(GC) cells in vivo and the mechanism involved. METHODS: E2F-1 recombinant lentiviral vectors were injected into xenograft tumors of MGC-803 cells in nude mice, and then tumor growth was investigated. Overexpression of transcription factor E2F-1 was assessed by reverse transcription-polymerase chain reaction(RT-PCR) and Western blotting analysis. Apoptosis rates were determined using a terminal deoxynucleotidyl transferase-mediated d UTP-biotin nick end labeling(TUNEL) assay. Expression levels of certain cell cycle regulators and apoptosis-related proteins, such as Bax, survivin, Bcl-2, cyclin D1, S-phase kinaseassociated protein 2, and c-Myc were examined by Western blotting and RT-PCR. RESULTS: Xenograft tumors of MGC-803 cells in nude mice injected with E2F-1 recombinant lentiviral vectors stably overexpressed the E2F-1 gene as measured by semi-quantitative RT-PCR(relative m RNA expression: 0.10 ± 0.02 vs 0.05 ± 0.02 for control vector and 0.06 ± 0.03 for no infection; both P < 0.01) and Western blotting(relative protein expression: 1.90 ± 0.05 vs 1.10 ± 0.03 in control vector infected and 1.11 ± 0.02 for no infection; both P < 0.01). The growth-curve of tumor volumes revealed that infection with E2F-1 recombinant lentiviral vectors significantly inhibited the growth of human GC xenografts(2.81 ± 1.02 vs 6.18 ± 1.15 in control vector infected and 5.87 ± 1.23 with no infection; both P < 0.05) at 15 d after treatment. TUNEL analysis demonstrated that E2F-1 overexpression promoted tumor cell apoptosis(18.6% ± 2.3% vs 6.7% ± 1.2% in control vector infected 6.3% ± 1.2% for no infection; both P < 0.05). Furthermore, lentiviral vector-mediated E2F-1 overexpression increased theexpression of Bax and suppressed survivin, Bcl-2, cyclin D1, Skp2, and c-Myc expression in tumor tissue.CONCLUSION: E2F-1 inhibits growth of GC cells via regulating multiple signaling pathways, and may play an important role in targeted therapy for GC.

Targeted therapy: resistance and re-sensitization

The last two decades have witnessed a paradigm shift from cytotoxic drugs to targeted therapy in medical oncol?ogy and pharmaceutical innovation. Inspired by breakthroughs in molecular and cellular biology, a number of novel synthesized chemical compounds and recombinant antibodies have been developed to selectively target oncogenic signaling pathways in a broad array of tumor types. Although targeted therapeutic agents show impressive clinical eicacy and minimized adverse efects compared with traditional treatments, the challenging drug?resistant issue has also emerged to limit their beneits to cancer patients. In this regard, we aim to improve targeted therapy by present?ing a systematic framework regarding the drug resistance mechanisms and alternative approaches to re?sensitize cancer cells/tissues therapeutically.

The absence of the ERBB4 hotspot mutations in melanomas in patients from southern China

V-erb-a erythroblastic leukemia viral oncogene homolog 4(ERBB4) has been reported to be somatically mutated in 19% of melanoma cases.To investigate the prevalence of ERBB4 mutations in melanoma patients from southern China,we analyzed 117 formalin-fixed,paraffin-embedded melanoma samples archived in the Sun Yat-sen University Cancer Center.A matrix-assisted laser desorption/ionization time-of-flight mass spectrometry(MALDI-TOF MS) platform was used to screen for mutations.No ERBB4 hotspot mutations were detected.Our results indicate that ERBB4 mutations may play a limited role in melanomas in China;therefore,targeting the ERBB4 mutation in melanoma patients from southern China may not be a promising strategy.

Mast Cells in Adjacent Normal Colon Mucosa rather than Those in Invasive Margin are Related to Progression of Colon Cancer

Objective: Mast cells (MC) reside in the mucosa of the digestive tract as the first line against bacteria and toxins. Clinical evidence has implied that the infiltration of mast cells in colorectal cancers is related to malignant phenotypes and a poor prognosis. This study compared the role of mast cells in adjacent normal colon mucosa and in the invasive margin during the progression of colon cancer. Methods: Specimens were obtained from 39 patients with colon adenomas and 155 patients with colon cancers treated at the Sun Yat-sen University Cancer Center between January 1999 and July 2004. The density of mast cells was scored by an immunohistochemical assay. The pattern of mast cell distribution and its relationship with clinicopathologic parameters and 5-year survival were analyzed. Results: The majority of mast cells were located in the adjacent normal colon mucosa, followed by the invasive margin and least in the cancer stroma. Mast cell count in adjacent normal colon mucosa (MCCadjacent) was associated with pathologic classification, distant metastases and hepatic metastases, although it was not a prognostic factor. In contrast, mast cell count in the invasive margin (MCCinvasive) was associated with neither the clinicopathlogic parameters nor overall survival. Conclusion: Mast cells in the adjacent normal colon mucosa were related to the progression of colon cancer, suggesting that mast cells might modulate tumor progression via a long-distance mechanism.

Longest survival with primary intracranial malignant melanoma:A case report and literature review

BACKGROUND Primary intracranial malignant melanoma(PIMM)is rare,and its prognosis is very poor.It is not clear what systematic treatment strategy can achieve long-term survival.This case study attempted to identify the optimal strategy for long-term survival outcomes by reviewing the PIMM patient with the longest survival following comprehensive treatment and by reviewing the related literature.CASE SUMMARY The patient is a 47-year-old Chinese man who suffered from dizziness and gait disturbance.He underwent surgery for right cerebellum melanoma and was subsequently diagnosed by pathology in June 2000.After the surgery,the patient received three cycles of chemotherapy but relapsed locally within 4 mo.Following the second surgery for total tumor resection,the patient received an injection of Newcastle disease virus-modified tumor vaccine,interferon,andβ-elemene treatment.The patient was tumor-free with a normal life for 21 years before the onset of the recurrence of melanoma without any symptoms in July 2021.A third gross-total resection with adjuvant radiotherapy and temozolomide therapy was performed.Brain magnetic resonance imaging showed no residual tumor or recurrence 3 mo after the 3rd operation,and the patient recovered well without neurological dysfunction until the last follow-up in June 2022,which was 22 years following the initial treatment.CONCLUSION It is important for patients with PIMM to receive comprehensive treatment to enable the application of the most appropriate treatment strategies.Long-term survival is not impossible in patients with these malignancies.

Translational medicine promising personalized therapy inoncology

Translational medicine has newly emerged to bridge the gap between bench-related basic science research and bedside clinical practice.From early diagnosis to late-stage disease treatment,translational medicine has transformed the clinical practice by making personalized medicine possible.Attributing to the progress in translational medical research,cancer therapy has evolved from non-specific cytotoxic drugs against both tumor and normal proliferating cells to more specific small molecule chemical and immunotherapy approaches.Small molecular agents are directed at unique pathogenesis of cancer cells,whereas immunotherapeutic agents target the cancer immune response.Both approaches aim to produce less toxicity with high effectiveness.Therapeutic regimens with these agents in biomarker-classified sensitive populations promises a personalized approach in modern oncology.