Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer

Abstract

Tumors with elevated c-Myc expression often exhibit a highly aggressive phenotype, and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cycle signaling can be therapeutically exploited to preferentially kill tumor cells. We therefore investigated whether exploiting elevated c-Myc expression is effective in treating esophageal cancer with the CDK inhibitor flavopiridol. We found frequent overexpression of c-Myc in human esophageal cancer cell lines and tissues. c-Myc overexpression correlated with accelerated esophageal cancer subcutaneous xenograft tumor growth. Esophageal cancer cells with elevated c-Myc expression were found preferentially more sensitive to induction of apoptosis by the CDK inhibition flavopiridol compared to esophageal cancer cells with lower c-Myc expression. In addition, we observed that flavopiridol alone or in combination with the chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with the targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth while significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to the CDK inhibitor flavopiridol, and that flavopiridol alone or in combination can be a potential therapy for c-Myc overexpressing esophageal cancer.

CDCA3 is a prognostic biomarker for cutaneous melanoma and is connected with immune infiltration

“…The underlying processes of CDCA3 in cutaneous melanoma should be clarified in further investigations. C-Myc and CyclinD1 are involved in cell cycle regulation, which might encourage metastasis of tumor cells ( 41 ). In the present study, western blot analysis was used to determine the relationship between CDCA3 and the expression of cell cycle protein markers.…”

Naa10p promotes cell invasiveness of esophageal cancer by coordinating the c-Myc and PAI1 regulatory axis

“…Moreover, the loss of c-Myc led to significant reductions in cell invasive abilities while overexpressing Naa10p significantly rescued the cell invasion of c-Myc-depleted ESCA cells, suggesting that this regulation axis may control cell invasiveness of ESCA cells. Although c-Myc has frequently reported to be overexpressed in ESCA and is recognized as a cancer marker, the prognostic significance of c-Myc expression levels in ESCA remains debated [ 34 , 35 ]. In fact, unlike the significant prognostic potential of NAA10 in ESCA, the expression of MYC did not correlate with patient survival when analyzing the TCGA ESCA database.…”

Strategies to target the cancer driver MYC in tumor cells

“…In esophageal cancer, MYC is aberrantly activated due to MYC gene amplification. Synthetic lethal interactions between MYC signaling and small-molecule inhibition involved in cell cycling have been therapeutically addressed to selectively kill tumor cells ( 180 ). Therefore, the flavonoid alkaloid CDK inhibitor alvocidib was applied in combination with nanoparticle albumin-bound paclitaxel to interfere with cell proliferation.…”