Molecular genomic features associated with <i>in vitro</i> response of the NCI‐60 cancer cell line panel to natural products

Krushkal, Julia; Negi, Simarjeet; Yee, Laura M.; Evans, Jason R.; Grkovic, Tanja; Palmisano, Alida; Fang, Jianwen; Sankaran, Hari; McShane, Lisa M.; Zhao, Yingdong; O’Keefe, Barry R.

doi:10.1002/1878-0261.12849

Cited by 18 publications

(15 citation statements)

References 154 publications

(263 reference statements)

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“…Alternative strategies leveraging this metabolic addiction have also been demonstrated via inhibiting glucose uptake preventing the conversion of potentially toxic cystine to cysteine [ 38 , 43 ]. This highly positive correlation (Spearman correlation coefficient ρ = 0.79, unadjusted p value = 1.07 × 10 –13 , FDR adjusted p value = 8.47 × 10 –8 ) demonstrates increased resistance of tumor cell lines to plumbagin associated with increased gene expression of SLC7A11, which is consistent with the previous findings by our group and other authors about the potential role of this transporter in resistance to multiple antitumor agents and natural products [ 29 , 38 , 42 , 44 ].…”

Section: Resultssupporting

confidence: 91%

“…Pre-treatment gene expression data for the NCI-60 cell lines was downloaded from the CellMinerCDB resource [ 23 , 28 ]. A more detailed description of the collection of molecular measures can be found in our previous publication [ 29 ]. For expression analysis, we used log 2 transformed expression measures of 23,059 annotated transcripts, lncRNAs, and miRNAs which had been previously combined from five Affymetrix expression microarray platforms and normalized by the CellMiner development team [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

“…The data were filtered using a list of candidate genes and functionally relevant SNVs from OncoKB v. 1.17, a curated precision oncology knowledge base [ 32 ]. As outlined in our earlier report [ 29 ], the list consisted of variants classified by OncoKB at levels 1–4 of potential therapeutic action, R1 and R2 levels of resistance, and variants classified as “oncogenic” and “likely oncogenic”. After applying this filter to the CellMiner WES data, 1,586 protein changing SNVs in 280 genes across 59 NCI-60 cell lines were identified.…”

Section: Methodsmentioning

confidence: 99%

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Pharmacogenomics of in vitro response of the NCI-60 cancer cell line panel to Indian natural products

et al. 2022

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Background Indian natural products have been anecdotally used for cancer treatment but with limited efficacy. To better understand their mechanism, we examined the publicly available data for the activity of Indian natural products in the NCI-60 cell line panel. Methods We examined associations of molecular genomic features in the well-characterized NCI-60 cancer cell line panel with in vitro response to treatment with 75 compounds derived from Indian plant-based natural products. We analyzed expression measures for annotated transcripts, lncRNAs, and miRNAs, and protein-changing single nucleotide variants in cancer-related genes. We also examined the similarities between cancer cell line response to Indian natural products and response to reference anti-tumor compounds recorded in a U.S. National Cancer Institute (NCI) Developmental Therapeutics Program database. Results Hierarchical clustering based on cell line response measures identified clustering of Phyllanthus and cucurbitacin products with known anti-tumor agents with anti-mitotic mechanisms of action. Curcumin and curcuminoids mostly clustered together. We found associations of response to Indian natural products with expression of multiple genes, notably including SLC7A11 involved in solute transport and ATAD3A and ATAD3B encoding mitochondrial ATPase proteins, as well as significant associations with functional single nucleotide variants, including BRAF V600E. Conclusion These findings suggest potential mechanisms of action and novel associations of in vitro response with gene expression and some cancer-related mutations that increase our understanding of these Indian natural products.

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Section: Resultssupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Pharmacogenomics of in vitro response of the NCI-60 cancer cell line panel to Indian natural products

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“…45,46 The flexibility of this tool allows correlation analysis for specific cancer cell lines, such as the specific tool focused on small cell lung cancer cell lines (SCLC-CellMiner) developed by Tlemsani et al 47 Recently, Krushkal et al, considering the importance of natural sources for new possible lead compounds, correlated the GI 50 values and protein expression data stored in NCI and CellMiner to elucidate the potential mechanism of action of numerous natural products (extracted from plants, marine invertebrates, and microbes). 48 The lack of recurring updates of the CellMiner database induced Arroyo and co-workers to download all the available data from NCI-60 and undertake large-scale screening to find a connection between standardized cancer cell line sensitivity to antiproliferative agents and corresponding standardized protein expression. The results obtained showed that the correlation between the antiproliferative activity of a given drug and the expression of a given protein could be exploited to: (i) confirm the biological target of known drugs; (ii) associate a mechanism of action with a new small molecule; (iii) repurpose an already developed drug against another target with which it is 'correlated'; (iv) explain the pleiotropic effects of drugs (multi/offtarget view); and (v) find targets that can be influenced by a given drug.…”

Section: In Silico Approaches Based On the Correlation Between Cell Line Chemosensitivity And Gene/protein Expression Patternmentioning

confidence: 99%

Identification of biological targets through the correlation between cell line chemosensitivity and protein expression pattern

Lauria

Monica

Gentile

et al. 2021

Drug Discovery Today

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“…Several thousand years ago, natural products were used for their medicinal properties (6), and increasing evidence has shown that natural products from vegetables, fruits and traditional medicines for anti-cancer research remains an important source of potentially novel treatments (7)(8)(9)(10)(11). Although there was a shift towards the study of synthetic drugs based on molecular biology and combinatorial chemistry, these synthetic drugs have the disadvantages of occasional intolerable side effects and expensive prices (12,13).…”

Section: Introductionmentioning

confidence: 99%

Regulation of the PTEN/PI3K/AKT pathway in RCC using the active compounds of natural products in vitro

et al. 2021

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Since Professor Tu Youyou won the 2015 Nobel Prize in Physiology and Medicine for the discovery of artemisinin, which is used to treat malaria, increased attention has been paid to the extracts obtained from plants, in order to analyze their biological activities, particularly with regard to their antitumor activity. Therefore, the present study explored the biochemical properties of seven natural plant extracts on renal cell carcinoma (RCC). 786-O and OS-RC-2 cells were cultured and treated with different concentrations of the extracts. Then, cell viability, the IC 50 value and proliferation was determined using a Cell Counting Kit-8 assay. Apoptosis and cell cycle distribution were evaluated via flow cytometry. The expression levels of proteins were assessed using western blotting, and cellular morphology was observed using a light microscope. The results showed that sophoricoside, aucubin, notoginsenoside R1 and ginsenoside Rg1 did not exhibit a cytotoxic effect on RCC cells, whereas ginsenoside Re and allicin exhibited a very slight inhibitory effect. Naringenin possessed the highest activity of the analyzed extracts. The IC 50 values of naringenin on 786-O and OS-RC-2 cells were 8.91±0.33 and 7.78±2.65 µM, respectively. In addition, naringenin notably inhibited the proliferation of RCC cells by decreasing Ki67 expression, blocked cell cycle progression in the G 2 phase by regulating expression of cell cycle proteins, and increased apoptosis by upregulating caspase-8 expression, downregulating Bcl-2 expression and altering the cellular morphology. Furthermore, naringenin inhibited cell proliferation and promoted apoptosis by upregulating the expression of PTEN at the protein level, downregulated the expression of PI3K and phosphorylated-(p-)AKT, but did not affect the expression of AKT, mTOR or p-mTOR. The seven plant extracts analyzed showed differing degrees of anti-RCC activity. Sophoricoside, aucubin, notoginsenoside R1 and ginsenoside Rg1 did not exhibit notable anti-RCC activity, whereas the effect of ginsenoside Re and allicin on RCC was considerably weak. However, naringenin showed potent anti-proliferative, apoptosis inducing and cell cycle arresting activity on RCC cells via regulation of the PTEN/PI3K/AKT signaling pathway.

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Molecular genomic features associated with in vitro response of the NCI‐60 cancer cell line panel to natural products

Cited by 18 publications

References 154 publications

Pharmacogenomics of in vitro response of the NCI-60 cancer cell line panel to Indian natural products

Pharmacogenomics of in vitro response of the NCI-60 cancer cell line panel to Indian natural products

Identification of biological targets through the correlation between cell line chemosensitivity and protein expression pattern

Regulation of the PTEN/PI3K/AKT pathway in RCC using the active compounds of natural products in vitro

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