TY - JOUR
T1 - Optimized combination of HDACI and TKI efficiently inhibits metabolic activity in renal cell carcinoma and overcomes sunitinib resistance
AU - Rausch, Magdalena
AU - Weiss, Andrea
AU - Zoetemelk, Marloes
AU - Piersma, Sander R.
AU - Jimenez, Connie R.
AU - van Beijnum, Judy R.
AU - Nowak-Sliwinska, Patrycja
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Clear cell renal cell carcinoma (ccRCC) is characterized by high histone deacetylase (HDAC) activity triggering both cell motility and the development of metastasis. Therefore, there is an unmet need to establish innovative strategies to advance the use of HDAC inhibitors (HDACIs). We selected a set of tyrosine kinase inhibitors (TKIs) and HDACIs to test them in combination, using the validated therapeutically guided multidrug optimization (TGMO) technique based on experimental testing and in silico data modeling. We determined a synergistic low-dose three-drug combination decreasing the cell metabolic activity in metastatic ccRCC cells, Caki-1, by over 80%. This drug combination induced apoptosis and showed anti-angiogenic activity, both in original Caki-1 and in sunitinib-resistant Caki-1 cells. Through phosphoproteomic analysis, we revealed additional targets to improve the translation of this combination in 3-D (co-)culture systems. Cell– cell and cell–environment interactions increased, reverting the invasive and metastatic phenotype of Caki-1 cells. Our data suggest that our optimized low-dose drug combination is highly effective in complex in vitro settings and promotes the activity of HDACIs.
AB - Clear cell renal cell carcinoma (ccRCC) is characterized by high histone deacetylase (HDAC) activity triggering both cell motility and the development of metastasis. Therefore, there is an unmet need to establish innovative strategies to advance the use of HDAC inhibitors (HDACIs). We selected a set of tyrosine kinase inhibitors (TKIs) and HDACIs to test them in combination, using the validated therapeutically guided multidrug optimization (TGMO) technique based on experimental testing and in silico data modeling. We determined a synergistic low-dose three-drug combination decreasing the cell metabolic activity in metastatic ccRCC cells, Caki-1, by over 80%. This drug combination induced apoptosis and showed anti-angiogenic activity, both in original Caki-1 and in sunitinib-resistant Caki-1 cells. Through phosphoproteomic analysis, we revealed additional targets to improve the translation of this combination in 3-D (co-)culture systems. Cell– cell and cell–environment interactions increased, reverting the invasive and metastatic phenotype of Caki-1 cells. Our data suggest that our optimized low-dose drug combination is highly effective in complex in vitro settings and promotes the activity of HDACIs.
KW - Drug–drug interaction
KW - HDAC inhibitor
KW - Multi-drug combination
KW - Renal cell carcinoma
KW - Therapeutically guided multidrug optimization (TGMO)
KW - Tyrosine kinase inhibitor
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85094612036&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/33126775
U2 - https://doi.org/10.3390/cancers12113172
DO - https://doi.org/10.3390/cancers12113172
M3 - Article
C2 - 33126775
SN - 2072-6694
VL - 12
SP - 1
EP - 22
JO - Cancers
JF - Cancers
IS - 11
M1 - 3172
ER -