Natural product therapy for KRAS/LKB1-mutant lung cancer: Luteolin, isolated from clover blossom, and Salvia tomentosa, increases the levels of tumor suppressor proteins, inhibits the expression of urea cycle enzyme carbamoyl phosphate synthetase-1 (CSP1), decreases pyrimidine pools, stalls DNA synthesis, and inhibits the progression of KRAS/LKB1-mutated lung cancers via up regulation of its target gene, 18/June/2017, 12.50 am

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Introduction: What they say

A study from the Children’s Medical Center Research Institute, UT Southwestern Medical Center, Dallas, Texas 75390, USA; Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas 75390, USA; and McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas 75390, USA shows that “CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells.” This research paper was published in the 1 June 2017 issue of the journal “Nature” [One of the best research journals in Biology with an I.F of 43+] by Prof. Ralph J. DeBerardinis, Jiyeon Kim, and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Natural product therapy for KRAS/LKB1-mutant lung cancer: Luteolin, isolated from clover blossom, and Salvia tomentosa,  increases the levels of tumor suppressor proteins, inhibits the expression of urea cycle enzyme carbamoyl phosphate synthetase-1 (CSP1), decreases pyrimidine pools, stalls DNA synthesis, and inhibits the progression of KRAS/LKB1-mutated lung cancers via up regulation of its target gene


From significance of the study to public health relevance:

Given that: (1) K-ras is mutated, amplified and overexpressed in a number of non-small-cell lung cancers (NSCLC); (2) Metabolic tumor suppressor protein LKB1 expression is lost in a number of cancers, including non-small-cell lung cancers; (3) even intense multimodal treatment saves only less than 50% of lung cancer patients; (4) our understanding is incomplete in terms of down stream molecular targets and the oncogenic/malignant pathways involved in K-ras-overexpressing or LKB1-lost cancers; (5) cancer causes the highest economic loss compared to all the known causes of death worldwide; and (6) K-ras-overexpressing cancer is a common occurance; and it results in considrable economic loss worldwide, there is an urgent need to find: (i) a cheaper alternative to the existing expensive drugs; (ii) a side-effect-free natural product-based drug; and (iii) a way to effectively treat and stall metastatic progression and relapse of k-ras-amplified/overexpressed or LKB1-lost cancers.


What is known?

A number of studies suggests that K-ras and LKB are frequently mutated or lost, respectively, in non-small-cell lung cancer (NSCLC).

Prof. Ralph J. DeBerardinis’s research team has recently shown that: (1) urea cycle enzyme carbamoyl phosphate synthetase-1 (CSP1) is overexpressed in K-ras overexpressing and LKB-mutated non-small-cell lung cancers (NSCLC); (2) LKB1 decreases CSP1 expression via induction of AMPK; (3) Loss of CPS1: (i) decreases Pyrimidine to purine ratio; (ii) stalls DNA-polymerase; (iii) inhibits S-phase progression; and (iv) induces DNA damage; (4) reduction of CSP1 levels promotes tumor cell death; and (5) treating tumors with exogenous Pyrimidines rescues both DNA damage and cellular growth, suggesting that decreasing the expression of CSP1 in NSCLC may induce tumor cell death.


From research findings to therapeutic opportunity:

This study suggests, for the first time, a natural product based therapy for KRAS/LKB1-mutant lung cancer. Luteolin, by decreasing the expression of its target genes, it may decrease the expression of CPS1. Thereby, it may: (1) decrease Pyrimidine to purine ratio; (2) stifle DNA-polymerase; (3) stall S-Phase progression; (4) induce DNA damage; and (5) stall tumor progression in non-small-cell lung cancer.

Figure 1. Mechanistic insights into how Luteolin inhibits CPS1 expression and stalls KRAS/LKB1-mutant lung cancer progression

Thus, pharmacological formulations encompassing “Luteolin  or its analogues, either alone or in combination with other drugs” may be used to treat KRAS/LKB1-mutant lung cancers.[easy_payment currency=”USD”]


Details of the research findings:

Idea Proposed/Formulated (with experimental evidence) by: Dr L Boominathan Ph.D.

Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/

Undisclosed mechanistic information: How Luteolin  inhibits the expression of CSP1 and stalls the progression of KRAS/LKB1-mutant lung cancers

Amount: $500#

# Research cooperation


References:

Citation: Boominathan, L.,  Natural product therapy for KRAS/LKB1-mutant lung cancer: Luteolin, isolated from clover blossom, and Salvia tomentosa,  increases the levels of tumor suppressor proteins, inhibits the expression of urea cycle enzyme carbamoyl phosphate synthetase-1 (CSP1), decreases pyrimidine pools, stalls DNA synthesis, and inhibits the progression of KRAS/LKB1-mutated lung cancers via up regulation of its target gene, 18/June/2017, 12.50 am, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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