TY - JOUR
T1 - Galunisertib synergistically potentiates the doxorubicin-mediated antitumor effect and kickstarts the immune system against aggressive lymphoma
AU - Rej, Abhinandan
AU - Paladhi, Ankush
AU - Daripa, Samrat
AU - Sarkar, Debanjan
AU - Bhattacharyya, Sankar
AU - Mondal, Indrani
AU - Hira, Sumit Kumar
N1 - Publisher Copyright:
© 2022 Elsevier B.V.
PY - 2023/1
Y1 - 2023/1
N2 - In clinical practice, major efforts are underway to identify appropriate drug combinations to boost anticancer activity while suppressing unwanted adverse effects. In this regard, we evaluated the efficacy of combination treatment with the widely used chemotherapeutic drug doxorubicin along with the TGFβRI inhibitor galunisertib (LY2157299) in aggressive B-cell non-Hodgkin lymphoma (B-NHL). The antiproliferative effects of these drugs as single agents or in combination against several B-NHL cell lines and the synergism of the drug combination were evaluated by calculating the combination index. To understand the putative molecular mechanism of drug synergism, the TGF-β and stress signaling pathways were analyzed after combination treatment. An aggressive lymphoma model was used to evaluate the anticancer activity and post-therapeutic immune response of the drug combination in vivo. Galunisertib sensitized various B-NHL cells to doxorubicin and in combination synergistically increased apoptosis. The antitumor activity of the drug combinations involved upregulation of p-P38 MAPK and inhibition of the TGF-β/Smad2/3 and PI3K/AKT signaling pathways. Combined drug treatment significantly reduced tumor growth and enhanced survival, indicating that the synergism between galunisertib and Dox observed in vitro was most likely retained in vivo. Based on the tumor-draining lymph node analysis, combination therapy results in better prognosis, including disappearance of disease-exacerbating regulatory T cells and prevention of CD8+ T-cell exhaustion by downregulating MDSCs. Galunisertib synergistically potentiates the doxorubicin-mediated antitumor effect without aggravating the toxic effects and the ability to kickstart the immune system, supporting the clinical relevance of targeting TGF-βRI in combination with doxorubicin against lymphoma.
AB - In clinical practice, major efforts are underway to identify appropriate drug combinations to boost anticancer activity while suppressing unwanted adverse effects. In this regard, we evaluated the efficacy of combination treatment with the widely used chemotherapeutic drug doxorubicin along with the TGFβRI inhibitor galunisertib (LY2157299) in aggressive B-cell non-Hodgkin lymphoma (B-NHL). The antiproliferative effects of these drugs as single agents or in combination against several B-NHL cell lines and the synergism of the drug combination were evaluated by calculating the combination index. To understand the putative molecular mechanism of drug synergism, the TGF-β and stress signaling pathways were analyzed after combination treatment. An aggressive lymphoma model was used to evaluate the anticancer activity and post-therapeutic immune response of the drug combination in vivo. Galunisertib sensitized various B-NHL cells to doxorubicin and in combination synergistically increased apoptosis. The antitumor activity of the drug combinations involved upregulation of p-P38 MAPK and inhibition of the TGF-β/Smad2/3 and PI3K/AKT signaling pathways. Combined drug treatment significantly reduced tumor growth and enhanced survival, indicating that the synergism between galunisertib and Dox observed in vitro was most likely retained in vivo. Based on the tumor-draining lymph node analysis, combination therapy results in better prognosis, including disappearance of disease-exacerbating regulatory T cells and prevention of CD8+ T-cell exhaustion by downregulating MDSCs. Galunisertib synergistically potentiates the doxorubicin-mediated antitumor effect without aggravating the toxic effects and the ability to kickstart the immune system, supporting the clinical relevance of targeting TGF-βRI in combination with doxorubicin against lymphoma.
KW - Apoptosis
KW - Cancer chemoprevention
KW - Lymphoma
KW - transforming growth factor beta (TGF‐β)
KW - Tumor immunology
UR - http://www.scopus.com/inward/record.url?scp=85145492012&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85145492012&partnerID=8YFLogxK
U2 - 10.1016/j.intimp.2022.109521
DO - 10.1016/j.intimp.2022.109521
M3 - Article
C2 - 36470118
AN - SCOPUS:85145492012
SN - 1567-5769
VL - 114
JO - International Immunopharmacology
JF - International Immunopharmacology
M1 - 109521
ER -