Disruption of Colorectal Cancer Network by Polyphyllins Reveals Pivotal Entities with Implications for Chemoimmunotherapy

The prevalence of colorectal cancer has increased world-wide with high rates of mortality and morbidity. In the absence of efficacious drugs to treat this neoplasia, there is an imminent need to discover molecules with multifaceted effects. To this end, we opted to study the effect of steroidal sapo...

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Main Authors: Ram Siripuram, Zinka Bartolek, Ketki Patil, Saj S. Gill, S. Balakrishna Pai
Format: Article
Language:English
Published: MDPI AG 2022-03-01
Series:Biomedicines
Subjects:
Online Access:https://www.mdpi.com/2227-9059/10/3/583
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author Ram Siripuram
Zinka Bartolek
Ketki Patil
Saj S. Gill
S. Balakrishna Pai
author_facet Ram Siripuram
Zinka Bartolek
Ketki Patil
Saj S. Gill
S. Balakrishna Pai
author_sort Ram Siripuram
collection DOAJ
description The prevalence of colorectal cancer has increased world-wide with high rates of mortality and morbidity. In the absence of efficacious drugs to treat this neoplasia, there is an imminent need to discover molecules with multifaceted effects. To this end, we opted to study the effect of steroidal saponins such as Polyphyllins. We performed anticancer activity studies with three analogs of Polyphyllins: Polyphyllin D (PD), Polyphyllin II (PII) and Polyphyllin G (PG). Here we show the potent effect of PD, PII (IC<sub>50</sub> of 0.5−1 µM) and PG (IC<sub>50 </sub>of 3 µM) in inhibiting the viability of colorectal adenocarcinoma cells (DLD-1) and colorectal carcinoma cells (HCT116). PD and PII also showed inhibition of cell proliferation and sustained response upon withdrawal of the compounds when assessed by clonogenic assays in both the cell lines. Elucidation of the molecular mode of action revealed impact on the programmed cell death pathway. Additionally, proteomic profiling of DLD-1 revealed pivotal proteins differentially regulated by PD and PII, including a downregulated peroxiredoxin-1 which is considered as one of the novel targets to combat colorectal cancers and an upregulated elongation factor 2 (EF2), one of the key molecules considered as a tumor associated antigen (TAA) in colon cancer. Entities of cell metabolic pathways including downregulation of the key enzyme Phosphoglycerate kinase 1 of the glycolytic pathway was also observed. Importantly, the fold changes per se of the key components has led to the loss of viability of the colorectal cancer cells. We envision that the multifaceted function of PD and PII against the proliferation of colorectal carcinoma cells could have potential for novel treatments such as chemoimmunotherapy for colorectal adenocarcinomas. Future studies to develop these compounds as potent anti-colorectal cancer agents are warranted.
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spelling doaj.art-fd798b9dc08b412e9b898e2fa4e94d452023-11-24T00:32:22ZengMDPI AGBiomedicines2227-90592022-03-0110358310.3390/biomedicines10030583Disruption of Colorectal Cancer Network by Polyphyllins Reveals Pivotal Entities with Implications for ChemoimmunotherapyRam Siripuram0Zinka Bartolek1Ketki Patil2Saj S. Gill3S. Balakrishna Pai4Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USAWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USAWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USAWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USAWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USAThe prevalence of colorectal cancer has increased world-wide with high rates of mortality and morbidity. In the absence of efficacious drugs to treat this neoplasia, there is an imminent need to discover molecules with multifaceted effects. To this end, we opted to study the effect of steroidal saponins such as Polyphyllins. We performed anticancer activity studies with three analogs of Polyphyllins: Polyphyllin D (PD), Polyphyllin II (PII) and Polyphyllin G (PG). Here we show the potent effect of PD, PII (IC<sub>50</sub> of 0.5−1 µM) and PG (IC<sub>50 </sub>of 3 µM) in inhibiting the viability of colorectal adenocarcinoma cells (DLD-1) and colorectal carcinoma cells (HCT116). PD and PII also showed inhibition of cell proliferation and sustained response upon withdrawal of the compounds when assessed by clonogenic assays in both the cell lines. Elucidation of the molecular mode of action revealed impact on the programmed cell death pathway. Additionally, proteomic profiling of DLD-1 revealed pivotal proteins differentially regulated by PD and PII, including a downregulated peroxiredoxin-1 which is considered as one of the novel targets to combat colorectal cancers and an upregulated elongation factor 2 (EF2), one of the key molecules considered as a tumor associated antigen (TAA) in colon cancer. Entities of cell metabolic pathways including downregulation of the key enzyme Phosphoglycerate kinase 1 of the glycolytic pathway was also observed. Importantly, the fold changes per se of the key components has led to the loss of viability of the colorectal cancer cells. We envision that the multifaceted function of PD and PII against the proliferation of colorectal carcinoma cells could have potential for novel treatments such as chemoimmunotherapy for colorectal adenocarcinomas. Future studies to develop these compounds as potent anti-colorectal cancer agents are warranted.https://www.mdpi.com/2227-9059/10/3/583Polyphyllin DPolyphyllin IIPolyphyllin GDLD-1HCT116proteomics
spellingShingle Ram Siripuram
Zinka Bartolek
Ketki Patil
Saj S. Gill
S. Balakrishna Pai
Disruption of Colorectal Cancer Network by Polyphyllins Reveals Pivotal Entities with Implications for Chemoimmunotherapy
Biomedicines
Polyphyllin D
Polyphyllin II
Polyphyllin G
DLD-1
HCT116
proteomics
title Disruption of Colorectal Cancer Network by Polyphyllins Reveals Pivotal Entities with Implications for Chemoimmunotherapy
title_full Disruption of Colorectal Cancer Network by Polyphyllins Reveals Pivotal Entities with Implications for Chemoimmunotherapy
title_fullStr Disruption of Colorectal Cancer Network by Polyphyllins Reveals Pivotal Entities with Implications for Chemoimmunotherapy
title_full_unstemmed Disruption of Colorectal Cancer Network by Polyphyllins Reveals Pivotal Entities with Implications for Chemoimmunotherapy
title_short Disruption of Colorectal Cancer Network by Polyphyllins Reveals Pivotal Entities with Implications for Chemoimmunotherapy
title_sort disruption of colorectal cancer network by polyphyllins reveals pivotal entities with implications for chemoimmunotherapy
topic Polyphyllin D
Polyphyllin II
Polyphyllin G
DLD-1
HCT116
proteomics
url https://www.mdpi.com/2227-9059/10/3/583
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AT ketkipatil disruptionofcolorectalcancernetworkbypolyphyllinsrevealspivotalentitieswithimplicationsforchemoimmunotherapy
AT sajsgill disruptionofcolorectalcancernetworkbypolyphyllinsrevealspivotalentitieswithimplicationsforchemoimmunotherapy
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