Anticancer drugs structure activity relationship of metformin

anticancer drugs structure activity relationship of metformin

Metformin is currently the first-line drug treatment for type 2 diabetes. . understanding of its structure-function relationships (Bridges et al., ), .. have shown direct antineoplastic activity of biguanides in model systems. Today, metformin is the 'gold standard' and drug of choice to treat patients .. Inhibition of mTOR may contribute to the anti-cancer activity of metformin; however, in vitro . Some studies have not been able to find a relationship between IR .. Johnson RA, Yeung SM, Stübner D, et al: Cation and structural. SNP, Sparcle, SRA, Structure, Taxonomy, ToolKit, ToolKitAll, ToolKitBookgh, UniGene Metformin is an antihyperglycemia drug and insulin sensitizer that improves . For diabetes-associated cancer, metformin prosecutes anticancer function . The authors have disclosed that they have no significant relationships with.

A lot of topological indices have been introduced recently for explaining different aspects of large molecules as e. As well known, the biological response is triggered when an appropriate simulating molecule docks with a receptor on the surface of the cell. In many cases the specific shape of the triggering molecule is not as important as its volume or surface area. The topological index could be ideal for evidencing the ability of the molecule to induce a particular biological response because it is well correlated with the surface area and volume.

It is not possible to discriminate between molecules having comparable skeleton but very different numbers of hydrogen atoms. A new index IP that overcomes these problems has been introduced by Popescu [15].

The new index is the sum of two components. The second one is calculated as the ratio of the number of hydrogen atoms to the number of atoms of the skeleton. The sum is normalized to the number of the atoms of the molecule.

A strong correlation between this new index and the anticancer activity of polycyclic hydrocarbons has been already revealed [15]. In this paper we report the calculation of the Randic normalized index and of the Popescu normalized index for a large number of antidiabetic drugs in order to show that these indices can discriminate between different classes of drugs and to correlate their values with the antidiabetic efficiency.

Building the clinical evidence on metformin and cancer - Cancerworld

We tried also to point out the correlation between structure and activity for some oral antidiabetic drugs whose hierarchy of the activity in reducing glucose has been already ascertained experimentally.

Methods and experimental data The branching index R can be easily calculated for a molecule using simple software and minimum computer resources. To calculate the index one assigns to each edge of a molecule hydrogen suppressed a value witch depends on the degrees of the vertices the edge connects.

The degree of any vertex is equal to the number of other vertices to which it is linked. The value is the product of the reciprocals of the square roots of the degrees of the vertices it joins.

The Popescu index was calculated on the basis of IR index.

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The ratio between the number of hydrogen and the total number of atoms was calculated and to this result was added the IR index. Finally, the sum was normalized to the total number of atoms in the molecule. The topological index, IP, was calculated for a series of antidiabetic drugs in the classes: Diabetes and inflammation Previously, certain researchers believed diabetes to be an inflammatory disease 49 — Metabolic disturbances and enhanced oxidative stress in patients with diabetes promote a continuous pro-inflammatory state, resulting in the decreased antioxidant capacity of cells.

Hypoimmunity of diabetic patients Patients with DM are more likely to have persistent infections, suggesting that these patients may be immunodeficient and therefore more susceptible to opportunistic infections Antitumor effect of metformin: Following this, metformin became recognized as the first-line treatment for diabetes due to its excellent hypoglycemic and cardiovascular protective effects.

Metformin and cancer: An existing drug for cancer prevention and therapy

InEvans et al 56in a case-controlled study that included 11, T2DM patients, identified for the first time that metformin may reduce the risk of cancer in patients with diabetes unadjusted odds ratio, 0. Ina population-based retrospective cohort study by Bowker et al 57 revealed that the metformin treatment group had a lower cancer-associated mortality rate compared with that of the sulfonylurea group and the insulin treatment group consisting of other patients with cancer and DM.

InEvans and colleagues re-highlighted the association between metformin treatment and tumorigenesis in patients with T2DM. The tumor incidence in 4, patients with diabetes treated with metformin was lower than that in the control group 7. A retrospective cohort study of 62, diabetic patients undertaken by Currie et al 60 demonstrated that monotherapy with metformin was associated with the lowest risk of solid tumor genesis compared with insulin or sulfonylurea treatment.

However, combined treatment with metformin and either insulin or sulfonylurea may reduce the insulin- or sulfonylurea-induced tumor risk. In the aforementioned study, it was observed that, compared with metformin treatment, insulin treatment increased the risk of colorectal and pancreatic cancer, and the HR was 1.

However, metformin therapy did not reduce the risk of breast or prostate cancer Additionally, another study revealed that metformin may reduce the risk of HCC in diabetic patients with chronic liver disease Ina prospectively-followed cohort study assessed the association between the use of metformin and cancer mortality in 1, patients with T2DM Metformin-treated patients were revealed to exhibit a reduced cancer mortality time compared with that of the controls with a median of 9.

Jiralerspong et al 65 observed that diabetic patients with breast cancer treated with metformin and neoadjuvant chemotherapy acquired a higher pathological complete response rate than those not being treated with metformin. The fact that the Add-Aspirin trial is now opening up in India could be seen as a third argument in favour of adding a metformin arm. Cancer prevention, including secondary prevention, needs to be a priority in countries where expensive high-tech treatments are accessible to only a privileged few.

  • Building the clinical evidence on metformin and cancer
  • Metformin and cancer: An existing drug for cancer prevention and therapy

None of which, Langley emphasises, rules out the possibility that metformin could also be of interest in other settings, including advanced disease. The trial compares a single standard-of-care arm against a rolling panel of exploratory treatments added to standard of care, and has recently started randomising patients to added metformin. Can metformin perform in advanced prostate cancer? Like Langley, Gillessen and all the STAMPEDE triallists spend a lot of time weighing up evidence to make intelligent decisions about the most likely options to move into large clinical trials — and with some notable successes.

The metformin arm of STAMPEDE is the tenth arm to run against a single continuously recruiting control arm, in a trial that has already notched up two important changes in the standard of care for men with advanced prostate cancer, first with docetaxel and more recently with abiraterone Eur Urology Gillessen believes that prostate cancer is a likely place to see a benefit from metformin, not least because it reduces insulin levels, which could be important for a number of reasons.

Those findings, says Gillessen, support the idea that metformin can work in patients who already have cancer, and not just in a prevention or adjuvant setting.

Whether or not that anti-cancer benefit shows up in the clinical trial only time will tell. This is because the androgen deprivation therapy that is the standard of care is believed to raise their risk of developing insulin resistance, high blood sugar levels, obesity, and high cholesterol, which may in turn raise their risk of diabetes and cardiovascular disease.

Is radiotherapy where metformin will prove its value? His priority is to follow up intriguing results from population and preclinical studies that seem to indicate a particular benefit when the drug is used in combination with radiotherapy.

anticancer drugs structure activity relationship of metformin

He too mentions the JCO study of 4, diabetic men treated for prostate cancer, which showed an association between cumulative dose of metformin and a significantly decreased risk of dying of that cancer, but points out that the decrease was a lot higher among the one in four men who had been treated with radiotherapy. A more recent study of 2, patients with local or locally advanced disease treated with curative radiotherapy including diabetics on metformin, diabetics not on metformin and non-diabetics showed that metformin was associated with improved biochemical PSA control and decreased incidence of castrate-resistant prostate cancer, distant metastases and prostate-specific cancer mortality Eur Urol These and other epidemiological studies — with all the many caveats — are backed up by evidence from mechanistic studies, including one conducted by Dal Pra and colleagues in the Koritzinsky Lab in Toronto, looking inter alia at the impact metformin has on cancer cell metabolism, and potential therapeutic implications Clin Cancer Res The relationship between hypoxia and resistance to radiotherapy has been known about for many years, he adds, but so far efforts to address the problem by increasing oxygen delivery to the cells have not gained significant clinical traction.

Metformin, by contrast, changes the way the cells consume oxygen, and may be more effective at combatting radio-resistance, he suggests. He worries, however, that the efforts of people like himself and his trial colleagues to learn more about exactly how and where metformin could play its most effective role in treating cancer may be hampered by lack of co-ordination. Could metformin work as an adjuvant? A meta-analysis of studies comparing outcomes between metformin users and non-metformin users for cancers treated curatively at an early stage found that, in colorectal cancer above leftmetformin use was associated with longer recurrence free survival, overall survival and cancer-specific survival.

For men with early-stage prostate cancer, metformin was also associated with significant, or borderline significant, benefits in all three outcomes, but there was significant heterogeneity between the studies above right.

anticancer drugs structure activity relationship of metformin

The data also suggest that prostate cancer patients treated with radical radiotherapy may benefit more from metformin. In breast and urothelial cancer, no significant benefits were identified.

C Coyle et al Ann Oncol Republished under a Creative Commons licence Who will take the lead?