Metformin in cancer prevention and therapy

Ann Transl Med. 2014 Jun; 2(6): 57.
doi: 10.3978/j.issn.2305-5839.2014.06.01
PMCID: PMC4200668
PMID: 25333032
Metformin in cancer prevention and therapy
Jacek Kasznicki,corresponding author Agnieszka Sliwinska, and Józef Drzewoski

Abstract
The prevalence of diabetes is dramatically increasing worldwide. The results of numerous epidemiological studies indicate that diabetic population is not only at increased risk of cardiovascular complications, but also at substantially higher risk of many forms of malignancies. The use of metformin, the most commonly prescribed drug for type 2 diabetes, was repeatedly associated with the decreased risk of the occurrence of various types of cancers, especially of pancreas and colon and hepatocellular carcinoma. This observation was also confirmed by the results of numerous meta-analyses. There are however, several unanswered questions regarding the exact mechanism of the anticancer effect of metformin as well as its activity against various types of cancer both in diabetic and nondiabetic populations. In the present work we discuss the proposed mechanism(s) of anticancer effect of metformin and preclinical and clinical data suggesting its anticancer effect in different populations.


The prevalence of diabetes is dramatically increasing worldwide reaching epidemic proportion. Landmark of diabetes, chronic hyperglycemia leads to the development and progression of life-treating complications, predominantly cardiovascular. The results of several studies indicate that people with diabetes (mainly type 2, T2DM) are also at substantially higher risk of cancer of the pancreas, liver, endometrium, breast, colon, rectum and urinary bladder compared to individuals without this chronic disease (1).

However, the incidence of other types of cancer (e.g., lung, kidney, non-Hodgkin lymphomas) does not seem to be strongly associated with diabetes or the evidence is inconclusive (2). Interestingly enough, it has been suggested that diabetes is associated with a lower risk for prostate cancer (2,3). According to the American Diabetes Association and the American Cancer Society consensus report the relative risks imparted by diabetes are greatest (about two fold or higher) for cancers of the liver, pancreas, and endometrium, and lesser (about 1.2-1.5 fold) for cancers of the colon and rectum, breast, and bladder (2).

Clinical observations indicate that the prevalence of diabetes in newly diagnosed cancer patients ranges from 8% to 18%, suggesting bidirectional association between these two disease (4,5). The association of diabetes and cancer was first reported as an incidental finding in 1932 (6). Nowadays, this coexistence is well recognized, however in spite of the intensive studies its mechanism still remains unclear. There is a general agreement that T2DM and cancer share several common potential risk factors (e.g., aging, sex, obesity, physical inactivity, diet, alcohol, and smoking).

In T2DM, insulin resistance and hyperinsulinemia (either endogenous due to insulin resistance or induced by administration of exogenous insulin formulations) are considered to be independent risk factors for cancer development (1,2). In addition, hyperglycemia-related oxidative stress, accumulation of advances glycation end products as well as low-grade inflammation may also enhance the risk of malignant transformation (7,8).

Recent publications have also suggested the link between hypoglycemic medications and cancer (8-11). The results of numerous preclinical, epidemiological and clinical studies suggested that metformin use is associated with inhibition of cancer cell growth and proliferation and reduction in all-cancer incidents in comparison with users of other hypoglycemic drugs. In the present work we discuss the proposed mechanism(s) of anticancer effect of metformin as well as preclinical and clinical data suggesting this beneficial effect.


Molecular action of metformin in cancer cell
The current proposed anticancer molecular action of metformin is mainly associated with the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). The mTOR pathway plays a pivotal role in metabolism, growth and proliferation of cancer cell (12). Metformin is thought to inhibit mTORC1 pathway (Figure 1).

It is believed that systemic effect of metformin manifested by the reduction of circulating level of insulin and insulin-like growth factor 1 (IGF-1) might be associated with anticancer action (13).

Insulin/IGF-1 is involved not only in regulation of glucose uptake but also in carcinogenesis through upregulation of insulin/IGF receptor signaling pathway (14).
The excessive food consumption (insulin) leads to increased liver production of IGF-1 that binds to IGF-1 receptor and insulin receptor.
Then, through insulin receptor substrate (IRS) the signal is transmitted to phosphoinositide 3-kinase (PI3K), and Akt/protein kinase B (PKB) that indirectly activates (not phosphorylates) mTORC1.
Additionally, insulin receptor through growth factor receptor-bound protein 2 (GRB2) propagates signal to Ras/Raf/ERK pathway that drives cell growth. Evidences indicate that these pathways play important role in changes of cellular metabolism that are typical feature of tumor cells (15).
Increased levels of circulating insulin/IGF1 and upregulation of insulin/IGF receptor signaling pathways were demonstrated to be involved in the formation of many types of cancer.
Metformin was found to reduce insulin level, inhibit insulin/IGF signaling pathways, and modify cellular metabolism in normal and cancer cells (16).

Evidences suggest that the inhibition of mTOR pathway by metformin proceeds dependent and independent on AMP-activated protein kinase (AMPK) activation.
AMPK phosphorylates tuberous sclerosis complex protein 2 (TSC2) that inhibits mTORC1 leading to decrease in protein synthesis and cell growth (17).
Among the first studies that showed the participation of AMPK activation in antitumor action of metformin were researches performed on breast cancer cells (18,19). Dowling et al. showed that compound C, an inhibitor of AMPK, reversed inhibition of initiation of translation evoked by metformin (18).
More recently, Mohammed et al. showed reduction of carcinoma spread in pancreas of transgenic mice fed with metformin (20). Additionally, pancreatic tissue of mice fed with metformin revealed a significant inhibition of mTOR, and an increase of phosphorylated AMPK and TSC2 (20). However, Gwinn el al. demonstrated that inhibition of mTOR could be independent on TSC2, since AMPK directly phosphorylates the rotor compartment of mTOR (21).

Several studies identified that liver kinase B1 (LKB1), a major upstream kinase of AMPK, may be involved in anticancer action of metfromin associated with inhibition of mTOR. In vitro and in vivo studies revealed that deletion of LKB1 function accelerated proliferation of tumor cell and sensitized them to activators of AMPK such as biguanide (22-24).
Due to the fact that p53 expression and phosphorylation is regulated by AMPK and p53 is involved in cell metabolism and control of cell cycle its participation in metformin action is discussed.
Growing evidences from in vivo and in vitro studies of various cancers revealed that metformin blocked cell cycle in G0/G1 phase with a significant decrease expression of G1 cyclins (including cyclin D1) without changes in p53 status (25-27).
However, others researches indicated that inhibitory effect on cancer cell growth of metformin was associated with p53 activity (28-31).
Taking together the results of preclinical studies are inconclusive whether antitumor action of metformin is associated with p53. Some investigators hypothesize that the dose of metformin may determine the effect of metformin. Yi et al. demonstrated on hepatoma cells that low concentration of metformin induced p53-dependent senescence, whereas higher doses induced apoptotic cell death (32).

Inhibition of mTOR by metformin independent on AMPK activation was demonstrated by Memmott et al. in mice lung cancer cells (16). Metformin evoked inhibition of mTOR pathway with accompanied decreasing activation of IGF-1/insulin receptor, Akt, extracellular signal-regulated kinase (ERK) without AMPK activation (16).
Kalender et al. demonstrated in Drosophilla cells that inhibition of mTOR signaling induced by metformin occurred in the absence of AMPK. They reveal the existence of an alternative TSC1/2-mTOR AMPK-independent pathway mediated by RAG GTPase (33).
Metformin was found to inhibit breast carcinoma cell growth through decreasing level of epidermal growth factor receptor 2 (HER2). This effect was mediated by inhibition of the mTOR effector, p70S6K1 (34).
p70S6K is responsible for the phosphorylation of S6 ribosomal protein and thereby protein synthesis at the ribosome (35). Antiproliferative action of metformin related to enhancement of DNA-damage-inducible transcript 4 protein (DDIT4, REDD1) expression, a negative regulator of mTOR, was reported in prostate cancer cells by Ben Sahra et al. (36).
This effect of metformin was also independent on AMPK activation (36).

The results of preclinical studies undoubtedly confirm the efficacy of metformin to inhibit cancer cell growth in vitro and to reduce tumor spread in animal models of various cancers. However, it should be stressed that molecular action of metformin is still investigated and seems to be affected by the type of tumor cell line.

Vitamin D Does Not Prevent Cancer

Medscape Medical News > Oncology News
Vitamin D Does Not Prevent Cancer: Study
Kristin Jenkins

July 24, 2018


The latest study on whether vitamin D can prevent cancer is negative, but there have been many such trials, and the findings have been contradictory.

The latest results come from New Zealand and are based on a post hoc analysis of the Vitamin D Assessment (ViDA) study, which involved 5108 community participants. The primary purpose of the ViDA study was to investigate cardiovascular outcomes.

It found that taking high doses of vitamin D for up to 4 years without calcium was not associated with reductions in cancer incidence or cancer mortality.

The cumulative incidence of cancer during a median follow-up of 3.3 years was 6.5% for those who received 100,000 IU of vitamin D3 each month. By comparison, the cumulative incidence of cancer during the same period was 6.4% among participants who received placebo (adjusted hazard ratio [HR], 1.01; P = .95).


"Monthly high-dose vitamin D supplementation may not be associated with cancer prevention and should not be used for this purpose," say Robert Scragg, MBBS, PhD, of the University of Auckland, and colleagues.

The report was published online July 19 in JAMA Oncology.

Scragg and colleagues note that other randomized clinical trials of vitamin D supplementation have provided inconsistent results. They point out that these latest results on cancer incidence are consistent with findings from previous randomized clinical trials of community samples from the United States and the United Kingdom, and they are also consistent with the results from a recent meta-analysis of vitamin D supplementation trials.

Considerable Interest
Approached for comment, Carolyn Y. Fang, PhD, coleader of Cancer Prevention and Control at Fox Chase Cancer Center in Philadelphia, Pennsylvania, said that in spite of the current study's null findings, "there is still considerable interest in the possible connection between vitamin D and cancer."


Clinicians should talk to patients who have vitamin D deficiency about how they can make healthy dietary or behavioral changes and whether taking a vitamin D supplement is warranted, Fang told Medscape Medical News.

"However," she added, "from a population health perspective, key questions regarding the appropriate 'dosage' of vitamin D for cancer prevention and how long one might need to take this dose in order to positively impact health remain to be addressed."

Conflicting Results
Results of previous studies on whether vitamin D can reduce cancer risk are conflicting.


In the largest and most comprehensive observational study to date, an international research group concluded that vitamin D was unlikely to provide primary prevention of lung cancer, even in nonsmokers.

Prior to that, the SUNSHINE study showed that high-dose vitamin D supplementation significantly improved progression-free survival in patients with advanced colorectal cancer who were receiving chemotherapy.

Last month, results from an international collaborative meta-analysis indicated that higher vitamin D levels in the blood may protect against colorectal cancer, especially in women.


In 2016, a literature review that included 28 new meta-analyses and 100 trials published between 2013 and 2017 revealed evidence that 10 to 20 μg daily of vitamin D can reduce death from any cause and death from cancer in middle-aged and older adults.

Study Details
The ViDA trial was a randomized, double-blind, placebo-controlled clinical trial that was conducted from March 1, 2011, to July 31, 2015. The primary outcome was the effect of vitamin D supplementation on the incidence of cardiovascular disease, but it also assessed possible effects related to acute respiratory infection, falls, and nonvertebral fractures.

Scragg and colleagues comment that findings from an earlier meta-analysis suggested that vitamin D supplements were "associated with a reduction in cancer mortality, but not cancer incidence."


The ViDA study participants were recruited from 55 family practices in Auckland. The mean age of the participants was 66 years, 58% were male, and 83% were of European or other race/ethnicity. The rest of the participants were of Polynesian or South Asian descent.

Of the participants, 320 (6.3%) used tobacco, and 2173 (42.5%) reported that they had formerly been smokers.

Some 1214 (23.8%) participants said they had been previously diagnosed with cancer. Cancer cases were evenly distributed between the two arms — of 2558 participants in the vitamin D group, 622 (24.3%) had been previously diagnosed with cancer, compared to 592 of 2550 (23.3%) patients in the placebo group.


Participants in the vitamin D group received an initial bolus of 200,000 IU of oral vitamin D3 followed by monthly doses of 100,000 IU. All participants were followed for up to 4.2 years.

At baseline, the mean concentration of deseasonalized 25-hydroxyvitamin D (25[OH]D) was 26.5 ng/mL. At follow-up, the mean concentration in a random sample of 438 participants was consistently higher than 20 ng/mL in participants taking vitamin D compared to those taking placebo.

The study showed that in 375 participants who were diagnosed with cancer after randomization, there were no differences in the percentage taking vitamin D vs placebo. The most common cancers included melanoma in situ, which was diagnosed in 71 participants, and malignant melanoma, which was diagnosed in 55 participants. Prostate cancer was diagnosed in 64 participants, colorectal cancer in 38, breast cancer in 36, and lymphoid and hematopoietic cancers in 36.

There were no significant differences between men and women, between participants with serum concentrations of 25(OH)D higher than 20 ng/mL vs lower than 20 ng/mL, or in the time to diagnosis after randomization. Similar results were seen for all secondary outcomes. These were defined as all malignant neoplasms reported from more than 12 months after randomization until the study medication was discontinued on July 31, 2015.

The fact that 25% of study participants had vitamin D deficiency may have limited the statistical power in that subgroup, the researchers indicate.

Funding for the study was provided by the Health Research Council of New Zealand. Dr Scragg and study coauthors have disclosed no relevant financial relationships.

JAMA Oncol. Published online July 19, 2018. Abstract

Nivolumab: EMA Extension of Indications

EMA Recommends Extension of Indications for Nivolumab

New indication concerns the treatment of locally advanced unresectable or metastatic urothelial carcinoma after failure of prior platinum-containing therapy
Date: 24 Apr 2017
Topic: Genitourinary cancers / Cancer Immunology and Immunotherapy
On 21 April 2017, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for the medicinal product nivolumab (Opdivo).

The marketing authorisation holder for this medicinal product is Bristol-Myers Squibb Pharma EEIG.

The CHMP adopted a new indication as follows:

“Opdivo as monotherapy is indicated for the treatment of locally advanced unresectable or metastatic urothelial carcinoma in adults after failure of prior platinum-containing therapy.”

For information, the full indications for Opdivo will be as follows:

“Melanoma
Opdivo as monotherapy or in combination with ipilimumab is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults.

Relative to nivolumab monotherapy, an increase in progression-free survival (PFS) for the combination of nivolumab with ipilimumab is established only in patients with low tumour PD-L1 expression.

Non-Small Cell Lung Cancer (NSCLC)
Opdivo as monotherapy is indicated for the treatment of locally advanced or metastatic non-small cell lung cancer after prior chemotherapy in adults.

Renal Cell Carcinoma (RCC)
Opdivo as monotherapy is indicated for the treatment of advanced renal cell carcinoma after prior therapy in adults.

Classical Hodgkin lymphoma (cHL)
Opdivo as monotherapy is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant (ASCT) and treatment with brentuximab vedotin.

Squamous Cell Cancer of the Head and Neck (SCCHN)
Opdivo as monotherapy is indicated for the treatment of squamous cell cancer of the head and neck in adults progressing on or after platinum-based therapy.

Urothelial Carcinoma
Opdivo as monotherapy is indicated for the treatment of locally advanced unresectable or metastatic urothelial carcinoma in adults after failure of prior platinum-containing therapy.”

Summaries of positive opinion are published without prejudice to the Commission decision, which will normally be issued 67 days from adoption of the opinion.

Detailed recommendations for the use of this product will be described in the updated summary of product characteristics, which will be published in the revised European public assessment report, and will be available in all official European Union languages after a decision on this change to the marketing authorisation has been granted by the European Commission.