Flavopiridol's effects on metastasis in KRAS mutant lung adenocarcinoma cells

Abstract

Background There is still no clinically approved agent for mutant KRAS, which is the most common alteration in non–small‐cell lung cancer (NSCLC). Flavopiridol is a semisynthetic flavonoid that inhibits cell growth through cyclin‐dependent kinases in G1/S or G2/M of the cell cycle and induces apoptosis. In this study, we evaluated its effect on cellular apoptosis, survival, and metastasis mechanisms on KRAS mutant A549, Calu‐1, and H2009 cell lines. Methods The cytotoxic effects of flavopiridol on NSCLC cells were determined by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide cell viability test. The cells were treated with 200 and 400 nM flavopiridol, and, then, apoptosis, survival, and metastasis‐related protein expressions were determined by Western blot analysis. The antimetastatic effects of flavopiridol were assessed by wound healing and Galectin‐3 activity assay. Results Flavopiridol drastically affected toxicity in all KRAS mutant NSCLC cells at nanomolar concentrations. Also, it could efficiently inhibit wound healing and Galectin‐3 activity in all the cells tested. However, the metastasis‐related protein expressions did not reflect these obvious effects on blotting. p‐Erk was activated as a cellular survival mechanism to escape apoptosis in all the cells tested. Conclusion Although there are many mechanisms that still need to be elucidated, flavopiridol can be used as a metastasis inhibitor and an apoptosis inducer in KRAS mutant NSCLC.

Cytotoxicity of combinations of the pan-KRAS SOS1 inhibitor BAY-293 against pancreatic cancer cell lines

“…The present tests revealed no activity of Bay-293 -Rapamycin combinations and Palbociclib was antagonistic in case of AsPC1. The pan-CDK inhibitor Flavopiridol was reported to exert marked toxicity in KRAS-mutated NSCLC cells [73]. Here, this compound synergized with Bay-293 for the KRAS-mutated cell lines but not for the wildtype BxPC3 cell line.…”

Cytotoxicity of combinations of the pan-KRAS inhibitor BAY-293 against primary non-small lung cancer cells

“…Combined inhibition of both MEK and CDK4/6 inhibitor Palbociclib was effective in preclinical models of KRAS mutant CRC and NSCLC [ 58 , 59 ]. The pan-CDK inhibitor Flavopiridol proved highly cytotoxic in all KRAS mutant NSCLC cells at nanomolar concentrations [60] . Furthermore, silencing of CDK4 induced senescence in NSCLC with KRAS-activating mutations [61] .…”

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

“…Synthetic lethal interaction with c-Myc overexpression has been observed with various targets including CDK (Yang et al, 2010;Horiuchi et al, 2012). Flavopiridol is a CDK inhibitor can have antiproliferative/proapoptotic effects in different cell lines through cell cycle arrest and by reducing c-Myc expression (Cobanoglu et al, 2016;Gokce et al, 2016;Dogan turacli et al, 2019). c-Myc overexpression has been reported in many cancer types including esophageal cancer (Tselepis et al, 2003;Dang, 2012;Jung et al, 2017;Wang et al, 2019) as we reported herein, and inhibiting CDK function using small molecule inhibitors (Senderowicz, 2003;Goel et al, 2020) sensitizing c-Myc overexpressing esophageal cancer cells to induce apoptosis can also be exploited.…”