


































Body Paragraph_Fang et al._Diabetes-Related Cancer.docx


Berkeley
Pharma Tech
Journal of Medicine

Correspondence: 
Robertfang17@gmail.com

Keywords:
Metabolic-reprogramming
Obesity
Diabetes
Metformin
Fasentin
Panitumumab

Submitted May 5, 2023 
Accepted July 7, 2023 
Published December 30, 2023

Full Open Access
Creative Commons

 Attribution License 4.0

Abstract
Cancer is a condition characterized by the uncontrolled growth and spreading of 
certain cells within the body. The formation of malignant tumors necessitates a 
substantial amount of energy to sustain the abnormal rate of cell division. This 
process leads to a significant alteration in the primary metabolic pathway, 
transitioning from mitochondrial respiration to aerobic glycolysis, particularly in 
cancers associated with diabetes. This shift creates an opportunity for less invasive 
treatment options that can limit cancer growth by targeting specific transporters and 
enzymes crucial for energy production. This article focuses on the biological functions 
of Fasentin and Metformin, exploring their effectiveness in constraining cancer 
development. The discussion delves into their roles in regulating metabolism and 
highlights how these drugs can be instrumental in impeding the progression of cancer.

Effective Reprogramming Strategies 
for Treating Diabetes-Related Cancer: 
A Focus on Fasentin, Metformin, and 
Panitumumab Therapies
By: Heyi Fang, Hailey Guinto, and Harshita Pinneboina



1. Introduction

Since its initial discovery, cancer has been one of the most formidable 
diseases. Though its early-stage symptoms are less virulent and the rate of 
recovery can be as high as 90%, advanced stages are faced with a high 
mortality rate. During intermediate and advanced stages, common 
treatments are invasive and seek to eradicate all cancer cells -- though 
recurrence is possible. If the cancer progresses to advanced stages, however, 
the mortality rate will quickly rise to 70% over the span of �ve years.1

There are various causes and risk factors for di�erent types of cancer, but 
chronic diseases2, high body mass index, (BMI) and unhealthy lifestyles 
appear as general components in all types. Diabetes mellitus, one of the 
most common chronic diseases, has proved to be positively correlated with 
the progression of cancer. Diabetes Mellitus refers to a group of diseases 
that a�ect how the body uses blood glucose with regulations by Insulin, 
adiponectin, leptin, and glucose transporter groups (GLUTs) that 
manipulates the metabolic �ux of metabolites between bloodstream and 
peripheral tissues with energy needs. Type I Diabetes will disable the 
pancreas from producing insulin and type II Diabetes is characterized by 
insulin resistance, which heavily impairs the patient's ability to utilize 
insulin for the regulation of sugar. Insulin is a hormone secreted by the 
pancreas and is used extensively for the metabolism of glucose and adipose 
tissue after food intake, especially for the synthesis of glycogen. Glucose is 
the major energy source and upon the damage of insulin's function, the 
homeostasis for glucose and glycogen is broken. Insulin also serves as a 
negative feedback signal for glycogenolysis, which transforms stored 
glycogen to free glucose. Moreover, more insulin circulating in the 
bloodstream will inhibit the synthesis of various proteins in di�erent 
tissues, interfering with normal physiological functions throughout the 
body, especially in the digestive system. In discussion of diabetes and the 
risk of faster cancer progression, diabetes provides extra energy supply to 
the uncontrolled dividing cancer cells, �lling the gap with an abnormally 
high consumption of energy. Heavily depending on the intake of energy, 
the shifted metabolic mechanism is a novel interest for the treatment of 
diabetes-related cancer. The complex energy transfer process including the

Berkeley Pharma Tech Journal of Medicine | 102



use of insulin, glucose transporter, and the change-of-function of many
metabolism-related cells in mitochondria are hypothesized as new aims
with a non-invasive treatment: treatment with no need of physical
insertion of instruments into the patient’s body. In this article, the
relationship among the chain of obesity, diabetes mellitus, and cancer
development researched by di�erent articles regarding to distinct
diabetes-associated cancer types is reviewed, the potential metabolic
reprogramming pathways of glucose uptake and digestion by cancer cells
are studied, and the mechanisms of inhibitory functions on process of
reprogramming by Fasentin, Panitumumab, and Metformin are possessed
for the possibility as drug treatments of diabetes-associated cancer.

2. Obesity and its Correlation to Diabetes Development
Obesity is considered a common risk factor for many diseases3. Regarding the
accumulation of excess adipose tissue, a Body Mass Index (BMI) of over 30
kg/m2 is utilized as an indicator. Obesity leads to metabolic disturbance, the
severe impairments of the ability to regulate the synthesis of adipocytokines
and the conversion between glucose and glycogen. Researchers have revealed
that common metabolic disturbances like dyslipidemia and hyperinsulinemia
are the causal factors of cancer development.

Many adipose cytokines are critical regulators for the maintenance of 
homeostasis between glucose and energy supply with some of them impacting 
a range of metabolic pathways to other organs. Two of the most intensively 
studied adipocytokines are adiponectin and leptin. While both are heavily 
impacted by the change in adiposity, the change in concentration and 
distribution of adipose tissue4 impacts the body’s response to metabolites. 
Adiponectin is secreted by adipose tissue into the bloodstream, with a function 
of mediating glucose metabolism and fatty acid oxidation process5. Study 
conducted by Reneau, James et al reveals that the linkage between the 
accumulation of adipose tissue and secretion of adiponectin shows a negative 
correlation6. Therefore, the increased adiposity inhibits the production of 
adiponectin, disabling its function to regulate gluconeogenesis6. Leptin, 
another cytokine secreted by adipose tissue, has an opposite e�ect to 
adiponectin. Acting on the central nervous system, namely the 
hypothalamus7,8, leptin serves to decrease the sense of hunger while inducing

Berkeley Pharma Tech Journal of Medicine | 103



the activity of beta pancreatic cells that produce insulin. It is shown that leptin
production is positively correlated with the increased adiposity, with a positive
feedback loop involving increased circulating insulin and the resulting increase
of adipose tissue. Both researched adipokines promote the risk of getting
diabetes.

Furthermore, insulin also plays a critical role in the hydrolyzation of fatty acid,
which serves to increase the rate of glucose uptake and fatty acid synthesis, as
well as decrease the rate of fatty acid decomposition9. The tumor, upon
receiving bene�cial signals from the adipose tissue, also feeds back with
inhibitory signals on the decomposition of fats. Therefore, a positive feedback
loop is observed among obesity-high blood insulin-tumor development, as
shown here in �gure 1.

Figure 1. The positive feedback of adipose tissue accumulation and cancer development.

For summary, the abnormally high BMI level indicates the obesity level of an 
individual, resulting in the �uctuation of production for critical metabolic 
regulators, which leads to the increasing level of insulin circulating in the body 
and subsequently, will cause Type II Diabetes Mellitus by inducing insulin 
resistance. Over time, the disturbance of homeostasis can generate enough 
energy to promote the growth of cancer, particularly in organs with high 
concentrations of adipose tissue.

3.  Type II Diabetes Mellitus (T2DM)    and its Correlation 
to Cancer Progression

Berkeley Pharma Tech Journal of Medicine | 104



The compilation of the mentioned negative impacts from the previous section
will lead to the development of T2DM. Establishment of insulin resistance
(IR) by tissues will be disabled to respond normally to the hormone insulin or
downregulate insulin receptors in response to hyperinsulinemia10. The detailed
development of IR remains unclear, but the hypothesis is that decrease in
insulin sensitivity with adjustments in the PI3K/Akt/mTOR signaling
pathway11.

Hyperinsulinemia boosts the advancement of cancer by providing access to
excess glucose from the bloodstream12. Normal functioning cells, upon
receiving glucose, will degrade it for energy with the assistance of oxygen in the
process of glycolysis, Citric Acid Cycle, and Oxidative Phosphorylation,
producing approximately 34 ATP per glucose used13. However, during the
pre-malignant expansion stage of tumor, the development of peripheral
Tumor Microenvironment (TME) will separate the interior of tumor cells
farther away from the local bloodstream14, which is the carrier of oxygen-rich
hemoglobin. The result of this isolation is the leveled average partial pressure of
oxygen in TME around 5 mmHg, which is only 12.5% in average of the venous
oxygen pressure15. This shift of oxygen level disallows cancer tissue to utilize
oxygen for the mitochondrial respiration process and instead, it switches its
dependence for energy to the Warburg E�ect, the metabolic reprogramming
e�ect done by tumor cells to rely on the energy provided by aerobic glycolysis.
This is only e�ective when there is an excessive supply of glucose and an
anaerobic environment, for the production of energy is only 4 ATP per glucose
consumed, rather ine�cient compared to the normal process16. Therefore, the
T2DM with its in�uence on tissues incapable of utilizing glucose e�ciently,
the extra circulating glucose in the bloodstream will be recruited and made use
of by the tumor complex17.

On the other hand, T2DM also provides conveniences for the progression of
cancer by the hyper-expressed insulin. Insulin serves as a mitogen in the human
body18. With high levels of insulin expressed, cells are excited by the signal from
mitogens to proceed with more mitosis. Besides insulin, Insulin-like Growth
Factor 1 (IGF1) also serves as an important mitogen. However, IGF1 is not
induced by the increased level of blood glucose, but the excess circulating
insulin serves to compete with IGF for the constant amount of IGF Binding

Berkeley Pharma Tech Journal of Medicine | 105



Protein 3 (IGFBP3). As IGF1 is a mitogen as well, the imbalance between 
IGF1-IGFBP3 ratio leads to excess proliferation of cancer cells. On top of that, 
IGFBP3 is considered a negative regulator of cancer as a low-penetrance tumor 
suppressor gene19.

4. The Role of Glucose Transporter (GLUT)           and 
Treatment with Fasentin and Panitumumab
The two mentioned changes negatively impact the in vivo microbiological

environment for all cancer types, because energy is a common restriction for
the development of all tumors. This has led the discussion to the molecular
metabolic pathway of energy generation, especially the relationship of blood
glucose and insulin level, as well as the mechanism of how glucose enters into
tissues.

In order for the intake of glucose to peripheral tissues from the bloodstream for 
further mitochondrial oxidation and ATP production, mammalian cells have 
developed a family of glucose transporter proteins for the transportation of 
sugar through the plasma membrane20. The abnormal blood glucose level 
within the T2DM patients will induce a stronger expression of GLUT families, 
especially in the energy-demanding tissue like adipose tissue and breast cells, 
the emphasis of our paper. There are 3 classes of GLUT, and the responsible 
group here is class I GLUT, which contains GLUT1-4 and GLUT1421. 
Di�erent GLUT types are responsible for the intake by di�erent tissues, and 
our emphasis will be on GLUT4, the one that controls uptake of glucose by 
skeletal muscle, cardiac muscle, and most importantly for cancer development, 
adipose tissue22.

The expression of GLUT4 is heavily regulated by the level of presenting 
insulin. Stored in intracellular vesicles, GLUT4 is released vesicular fusion once 
insulin binds with the insulin receptors expressed on the plasma membrane23. 
Increased GLUT4 availability to glucose in the bloodstream causes more 
glucose uptake by fat. This is thought to be the e�ort against the development 
of Insulin Resistance, although it also promotes the creation of a positive 
feedback loop for fat accumulation and development of diabetes22. This has led

Berkeley Pharma Tech Journal of Medicine | 106



the research interest to a potential drug that restricts metabolic e�ciency of
cancer cells by inhibiting the process of glucose intake.

There are two potential targets in regard to this possible map. First, the insulin
receptors are Receptor Tyrosine Kinase (RTK), which requires the process of
dimerization and phosphorylation to the transduction of the chemical
substances from ligands to intracellular electric signals24. This is not unique
because many signal regulation pathways utilize RTK as well, and they can also
be seen as targets. Therefore, a potential therapy is to block or terminate the
phosphorylation process of RTKs with pharmaceutical interventions. There
are already drugs developed for cancer treatments via this pathway, namely the
Panitumumab25. Panitumumab is an agent serving to restrict progression of
colorectal cancer on epithelial level26. Epithelial cancer is a critical cancer type
that is a�ected by T2DM, for the transformation of normal epithelial to
cancerous cells requires enormous amounts of energy consumption.
Panitumumab inhibits the function of Epithelial-Growth Factor Receptor
(EGFR), which after cancerous lesion, starts the process of uncontrolled
replication27. Panitumumab, by binding to the extracellular receptor of EGFR
and outcompeting the essential nutrients for cell proliferation, e�ectively
inhibits the progression. Recently, clinical trials were made with Panitumumab
on its pharmaceutical e�ect on cancer types other than colorectal cancer.
Records show that it can also repress the development of head cancer and neck
cancer28.

Secondly, the drug can also target the intake of glucose by the direct blockage
of GLUT4. Fasentin serves 2 functions for the suppression of tumor
establishment. Firstly, Fasentin is a direct inhibitor of GLUT4. By
outcompeting the glucose on binding a�nity represented by a higher IC50
value29, Fasentin e�ectively reduces the glucose uptake by cancer-surrounding
tissue and therefore, an inhibitory e�ort is made to reduce energy production.
Secondly, Fasentin presence serves as a stimulatory signal for the activation of
Fas-directed apoptosis process of cancer30. Therefore, intake of Fasentin can
both directly, by inducing cancer cell death by apoptosis and indirectly, by
restricting the amount of glucose in�ow.

Berkeley Pharma Tech Journal of Medicine | 107



5. Treatment Incorporating Monocarboxylate Transporter 4 
and Cannabinoid Receptor 2
The distorted glucose in cancer cells results in the upregulation of glycolysis in 
cancer cells. This induces a high amount of lactate production, and 
consequently, its accumulation in these cells. Blocking upregulation of aerobic 
glycolysis has been ine�ective, such as using 2-DG as an anti-cancer agent. 
Mere inhibition of glycolysis is insu�cient for the eradication of cancer cells 
due to the reason that cancer cells have the potential to adapt their 
metabolism to their environmental conditions. Upon glycolytic suppression in 
multiple types of tumor cells, intracellular energy metabolism is 
reprogrammed in an autophagy-dependent manner to ensure cellular 
survival.

Rather, a possible treatment method for these cancer cells is aggravation into a 
hyper-glycemic condition, followed by blocking products from TCA 
cycle, resulting in high amounts of lactate production. This lactate export 
is then blocked, causing intracellular acidi�cation and consequently cell 
death. The high amount of lactate can cause a strong acidi�cation process, in 
which most of the normal cell functions are inhibited, including 
division. The high amount of lactate can cause a strong acidi�cation process, 
in which most of the normal cell functions are inhibited, including 
division. In addition, lactate released from tumor cells through 
Monocarboxylate Transporter 4 (MCT4) is enough to stimulate angiogenesis 
and tumor growth. Increased lactic acid can in turn enhance glycolysis in 
cancer cells, causing a vicious cycle. However, this high lactate content causes 
normal cell functions to be inhibited, including the process of replication and 
division.

Using this manner, a treatment of poisoning the cancer cells is feasible by 
inducing over-production of lactate to decrease pH level. However, research 
shows that a highly acidic environment surrounding the tumor is responsible 
for the development of chemotherapy resistance. Thus, two needs that must 
be met are to increase lactate formation and block the lactate from exiting 
the cancer cell.

A potential pathway of this treatment is the utilization of Monocarboxylate 
Transporter 4 (MCT4) along with the cannabinoid receptor 2 (CB2).31

Berkeley Pharma Tech Journal of Medicine | 108



Monocarboxylate transporter 4 (MCT4) is highly expressed in metastatic
tumors and at in�ammatory sites, referentially in glycolytic muscle �bers and
facilitating the lactate e�ux. MCT4 is responsible for the bidirectional
transport of lactate across the plasma membrane. The CB2 receptor modulates
immune cell functions. Cannabinoid receptors (CB1 and CB2)– G-protein
coupled receptors, inhibit adenylate cyclase activity in response to psychoactive
cannabinoids32. The activation of CB2 receptors does not appear to produce
psychotropic e�ects, and therefore, it may also be helpful in treating diseases
that have a neuroin�ammatory or neurodegenerative component, such as
multiple sclerosis.

MAPKs are enzymes involved in a wide variety of important signaling cascades
in many cellular responses– cell proliferation, migration, transformation, and
cell death. MAPK activation by a nonselective CB2 receptor agonist
(D9-THC) was found to have a proapoptotic e�ect in the Jurkat human
leukemia cell line (Herrera et al., 2005) and cytotoxicity in J774-1
macrophages; In the same cells, there was also a c-Jun N-terminal
kinase–mediated cytoprotective e�ect mediated by Δ9-THC activation of CB2
receptors, displaying the same CB2 receptor ligand can activate multiple
MAPKs, each with di�erent outcomes33.

The activation of CB2 receptors by natural or synthetic ligands favors a range
of receptor conformations that can variably a�ect di�erent signaling pathways
as the following procedure– inhibition of adenylyl cyclase, decreased cAMP
(production, and less activation of cAMP-dependent protein kinase (PKA),
inhibiting A-type potassium channels as well as speci�c gene expression. This is
followed by activation of Akt/protein kinase B– stimulating cell survival,
migration, and growth. Proceeding activation of the mitogen-activated protein
kinase (MAPK) cascade favors cell survival and modulates gene expression. In
addition, there is inhibition of speci�c calcium channels and enhanced opening
of G protein–gated inwardly rectifying potassium (GIRK) channels. Lastly,
stimulation of de novo synthesis of ceramide and inhibition of the MAPK
cascade promotes apoptosis34,35. Recruitment of b-arrestin to the activated CB2
receptor results in desensitization and/or internalization of the receptor and
potential activation of arrestin-speci�c signaling. Decreased PKA activity
increases Raf-1 to stimulate the MAPK cascade, positively regulating the

Berkeley Pharma Tech Journal of Medicine | 109



expression of many genes and indicating activation of a pathway by CB2
receptor agonists. Functional selectivity of CB2 receptor agonists must be
considered during the therapeutic development of CB2 agonists, which
increases the possibilities for developing drugs targeting CB2 receptors.

By forcing glycolysis with metformin and a NF-kB inhibitor lowers the pH of a
cell, our treatment has a minor e�ect on normal cells and most e�ective in
cancer patients with any hyperglycemic stages, including. As an example,
NK-kB inhibition causes increased lactate secretion from breast cancer cell line
MCF-736,37. The e�ect of this metabolic reprogramming strategy was observed
by checking oxygen consumption and extracellular acidi�cation rates. This
resulted in reduced OCR and blocked ECAR, essentially leading to an
accumulation of lactate. Fluorescent BCFL-AM was used as a probe for
detecting pHi. Therefore, the reprogramming did not decrease viability in
(normal) MCF-12A cells. It did, however, a�ect MCF-7, T47D, and
MDA-MB-231 (breast cancer cells), demonstrating signi�cantly inhibited
migration and invasion ability38. Consequently, in high glucose cancer cells, a
higher glycolysis rate is present, allowing the reprogramming strategy to further
promote the process and raise intracellular lactate, permitting cancer cells to
poison themselves. Essentially, there is limited cytotoxic e�ect on non-subject
cells, reducing the chance of untargeted damage.

CB-2 might bind to a pocket of MCT4 composed of Ser156, Phe243, Tyr332,
Gln339 and Glu363. The combination of Metformin and CB-2 exerts a
deleterious e�ect on breast cancer cell viability and exhibits synergistic
antitumor e�ects. Results of the combination treatment showed a 63%
inhibition of cell viability in MDA-MB-231 breast cancer cells39. In addition,
moderate e�ect on cell viability was observed in normal MCF-10A human
mammary epithelial cells. Disrupting MCT4 function leads to an
accumulation of intracellular lactate and a decrease in intracellular pH which
may rapidly damage a cell thereby inducing necrosis, apoptosis or growth
arrest. Metformin increases glycolysis thereby increasing the buildup of
intracellular lactate, thereby accelerating the e�ects of the MCT4 inhibitor.
This can be used to treat high glycolytic rate/MCT4-expressing malignancies.
Another possible combination is the MCT4 inhibitor CB-2 and a GLS1
inhibitor CB-839 to reengineer cancer metabolism40. This combination solves

Berkeley Pharma Tech Journal of Medicine | 110



the problem of increasing ammonia production to neutralize lactate via 
restricting the metabolic �exibility of these cancer cells.

6. Metformin to Target Cancer Cells’ Glucose Metabolism 
and mTOR Pathway
The collection of genetic alterations in cancer cells causes interference with the 
regular cellular signaling pathways, this then leads to cell growth for cancer. 
Despite the di�erent current treatment plans that are o�ered, many recoveries 
fail due to the drug resistance and its adverse side e�ects. Though in recent 
studies, metabolic reprogramming has served as a possible cancer therapy. With 
this, we want to identify the glucose metabolism of cancer cells to alter so it 
causes glucose-lowering agents like metformin to be a possible treatment in 
cancer cells.

One change we can see in cancer metabolism is known as the Warburg e�ect. 
The metabolic adaptation shifts their energy production from oxidative 
phosphorylation in the process of aerobic glycolysis. Metformin is a commonly 
prescribed drug used for type 2 diabetes, which also displays anticancer 
properties in inhibiting mitochondrial complex I,41,42 activating AMPK, a 
regulator for energy metabolism, and reducing insulin and insulin-like growth 
factor 1 (IGF-1), which performs anti-tumor functions. In addition, 
Metformin has shown ability to inhibit the mTOR pathway, which is involved 
in the protein synthesis and cell growth process. There are two types of forms 
of mTOR: complex 1 (mTORC1) used in growth factors, glucose, and helps 
with protein synthesis; and complex 2 (mTORC1) used for regulating cell 
survival and metabolism43.

Metformin inhibits mTORC1 which then activates AMPK and 
phosphorylates the TSC2 protein, the negative regulator of mTOC1. This 
inhibition can occur both dependent and independent of AMP-activated 
protein kinase (AMPK) activation, leading to the decrease in protein synthesis 
and cell growth. Metformin is able to inhibit mTORC1 independently when 
AMPK is activated as it is binding to the complex.43 This dual mechanism 
causes a positive treatment for the host, since metformin has multiple strategies 
to repress pathways critical for cancer cell growth.

Berkeley Pharma Tech Journal of Medicine | 111



Recent studies with mice given metformin after being exposed to carcinogen
show a reduction of lung tumor burden by up to 53%. However, only modest
e�ects presented as mTOR was inhibited in lung tumors 45. The researchers
then inject mice with metformin to assess whether this method would improve
mTOR inhibition. The result shows that plasma levels of metformin were
higher after injection than oral administration. On the other hand, Metformin
also activates AMPK and inhibits mTOR in liver tissue, but it only inhibits
phosphorylation process of IGF-IR/IR, Akt, ERK, and mTOR in lung tissue.
This suggests that Metformin indirectly inhibited mTOR in lung tissue by
decreasing activation of IGF-1R/IR and Akt upstream of mTOR45. A
follow-up study showed that intraperitoneal administration of metformin
decreased tumor burden by 72%, which correlates with decreased cellular
proliferation and marked inhibition of mTOR in tumors, as shown in �gure 2.

Figure 2. As the intake ofMetformin treatment inhibits plasma IGF-1 level in all tissues. As

mentioned, theMetformin inhibition also has specificity in lung and liver tissue.

Metformin swords decrease with the phosphorylation of IGF-1 and the insulin
receptors in lung tissues. The drug is known for reducing the levels of
hormones presentation in patients. With oral administration of Metformin,
study shows a decrease of 1 or 5 mg/ml of circulating IGF-1 by approximately
20% and the insulin by 20% and 35%44.

Berkeley Pharma Tech Journal of Medicine | 112



There was an injection of metformin intraperitoneally to assess its inhibitory
e�ect on mTOR pathway. However, the intraperitoneal injection did not
decrease the IGF-I levels signi�cantly. Instead, the levels of IGF-1 inside the
mice shows a signi�cant reduction from the wild type comparison group. This
can indicate that stress in daily injection can alter the masked inhibitory e�ect
of metformin in circulating the levels of IGF-1. This supports the hypothesis
that metformin can be used in mTOR pathways with cancer patients, since it
will decrease the levels of circulating IGF-1 (insulin) in preventing the
NNK-induced lung tumorigenesis45.

In addition to its ability to inhibit the mTOR pathway, Metformin triggers a
decrease in cap-dependent translation. A study utilizes MCF-7 cells,
Metformin treatment and led to a maximal inhibition of 40% in cap-dependent
translation45. The polysome pro�le analysis shows how the metformin
treatment of MCF-7 cells leads to a shift of mRNAs from heavy to light
polysomes and how concomitant increased 80s ribosomes46. This suggests that
metformin can be a treat and cause signi�cant impact on the translation of
speci�c mRNAs and leads to alteration of protein expression in cancer cells.
The change in polysome pro�les towards lighter polysomes indicates a
reduction in the translation e�ciency of speci�c mRNAs. This can help with
further implication for cancer cells that rely on increased protein synthesis for
their survival and proliferation47. The increase of 80s ribosomes indicates that
Metformin treatment may also a�ect the biogenesis of ribosomes, which is
essential for protein synthesis. This decreases the rate of protein synthesis
within cancer hosts, which can then be added to the growing body of evidence
supporting the potential of Metformin as a therapeutic agent for cancer.

In MCF-7 breast cancer cells, Metformin has been shown to inhibit translation
initiation by activating SMP-activated protein kinase (AMPK) through its
upstream kinase, liver kinase b1 (LKB1)48. This results in the inhibition of the
mammalian target of mTORC1. Although in contrast, in MDA-MB-231
breast cancer cells, didn’t express LKB1 mRNA, metformin had no e�ect on
its protein synthesis, con�rming the requirement of LKB1 for inhibition of
translation by metformin in MCR-7 breast cancer cells49. This con�rms the
requirement of LKB1 for inhibition of translation by metformin in MCF-7

Berkeley Pharma Tech Journal of Medicine | 113



breast cancer cells. It is an important biomarker for predicting the response to 
metformin treatment.

7. Conclusion
As discussed, the development of diabetes is a result of imbalance between 
glucose metabolism and anabolism. This distorted metabolic system can be 
caused by abnormally increased glucose intake and the subsequent 
development of insulin resistance, causing T2DM. Furthermore, the 
establishment of T2DM, along with an anaerobic environment that is 
bene�cial for the cancer progression, will reshape the metabolic dependence of 
tumor from mitochondrial respiration to aerobic glycolysis. Extensive supply 
of glucose can be advantageous for cancers with high energy demand to ful�ll 
its need of rapid division and proliferation. Therefore, a new target for 
non-invasive cancer treatment emerges. By limiting the energy in�ux to tumor 
tissue with either direct blockage on membrane receptors or indirect pathways 
that induce speci�c cell killing, three of the potential candidates are available 
for consideration, which are Panitumumab, Fasentin, and Metformin. Even 
though all the mentioned treatments are proven to be e�ective to some extent, 
assistance from corresponding drugs and therapies is highly recommended 
since some of the directed pathways are not exclusive to cancer, which leaves 
potential risk of a�ecting normal cell functioning. Moreover, many of the 
mentioned pathways are distinct from each other, which gives the possibility of 
combinational use, similar to a cocktail therapy for HIV patients50.

Berkeley Pharma Tech Journal of Medicine | 114



References

1. World Health Organization, Cancer
Overview. https://www.who.int/news-room
/fact-sheets/detail/cancer

2. Tu H,Wen CP, Tsai SP, et al. Cancer risk associated
with chronic diseases and disease markers: prospective
cohort study. BMJ. 2018;360:k134. Published 2018 Jan
31. doi:10.1136/bmj.k134

3. Kitabchi AE, Umpierrez GE, Miles JM,
Fisher JN. Hyperglycemic crises in adult
patients with diabetes. Diabetes Care.
2009;32(7):1335-1343. doi:10.2337/dc09-9032

4. Ghoshal, K., Chatterjee, T., Chowdhury, S.
et al. Adiponectin Genetic Variant and
Expression Coupled with Lipid Peroxidation
Reveal New Signatures in Diabetic
Dyslipidemia. BiochemGenet 59, 781–798
(2021).
https://doi.org/10.1007/s10528-021-10030-5

5. Reneau, James et al. “E�ect of adiposity on
tissue-speci�c adiponectin secretion.” PloS
one vol. 13,6 e0198889. 20 Jun. 2018,
doi:10.1371/journal.pone.0198889

6. Margetic, S et al. “Leptin: a review of its
peripheral actions and interactions.”
International journal of obesity and related
metabolic disorders : journal of the International
Association for the Study of Obesity vol. 26,11
(2002): 1407-33. doi:10.1038/sj.ijo.0802142

7. Dimitriadis, George et al. “Insulin e�ects in
muscle and adipose tissue.” Diabetes research and
clinical practice vol. 93 Suppl 1 (2011): S52-9.
doi:10.1016/S0168-8227(11)70014-6

8. Forny-Germano L, De Felice FG, Vieira

MNDN. The Role of Leptin and Adiponectin in
Obesity-Associated Cognitive Decline and
Alzheimer's Disease. Front Neurosci.
2019;12:1027. Published 2019 Jan 14.
doi:10.3389/fnins.2018.01027

9. Kennedy A, Gettys TW,Watson P, et al. The
metabolic signi�cance of leptin in humans:
gender-based di�erences in relationship to
adiposity, insulin sensitivity, and energy
expenditure. J Clin Endocrinol Metab.
1997;82(4):1293-1300.
doi:10.1210/jcem.82.4.3859

10. Wang, Guanyu. “Singularity analysis of the
AKT signaling pathway reveals connections
between cancer and metabolic diseases.” Physical
biology vol. 7,4 046015. 22 Dec. 2010,
doi:10.1088/1478-3975/7/4/046015

11. Gatenby, R., Gillies, R. Why do cancers have
high aerobic glycolysis?. Nat Rev Cancer 4,
891–899 (2004).
https://doi.org/10.1038/nrc1478

12. Del Puerto-Nevado L, Santiago-Hernandez A,
Solanes-Casado S, et al. Diabetes-mediated
promotion of colon mucosa carcinogenesis is
associated with mitochondrial dysfunction. Mol
Oncol. 2019;13(9):1887-1897.
doi:10.1002/1878-0261.12531

13. Zhang, Daoxiang et al. “Metabolic
reprogramming of cancer-associated �broblasts by
IDH3α downregulation.” Cell reports vol. 10,8
(2015): 1335-48.
doi:10.1016/j.celrep.2015.02.006

14. Neophytou CM, Panagi M, Stylianopoulos T,
Papageorgis P. The Role of Tumor
Microenvironment in Cancer Metastasis:
Molecular Mechanisms and Therapeutic

Berkeley Pharma Tech Journal of Medicine | 115



Opportunities. Cancers (Basel). 2021;13(9):2053.
Published 2021 Apr 23.
doi:10.3390/cancers13092053

15. Vander Heiden, Matthew G et al.
“Understanding theWarburg e�ect: the metabolic
requirements of cell proliferation.” Science (New
York, N.Y.) vol. 324,5930 (2009): 1029-33.
doi:10.1126/science.1160809

16. Jogie-Brahim, Sherryline et al. “Unraveling
insulin-like growth factor binding protein-3
actions in human disease.” Endocrine reviews vol.
30,5 (2009): 417-37. doi:10.1210/er.2008-0028

17. Olson, A L, and J E Pessin. “Structure,
function, and regulation of the mammalian
facilitative glucose transporter gene family.”
Annual review of nutrition vol. 16 (1996):
235-56.
doi:10.1146/annurev.nu.16.070196.001315

18. Call R, Grimsley M, Cadwallader L, et al.
Insulin--carcinogen or mitogen? Preclinical and
clinical evidence from prostate, breast, pancreatic,
and colorectal cancer research. PostgradMed.
2010;122(3):158-165.
doi:10.3810/pgm.2010.05.2153

19. Bell, G I et al. “Molecular biology of
mammalian glucose transporters.” Diabetes care
vol. 13,3 (1990): 198-208.
doi:10.2337/diacare.13.3.198

20. Shepherd, P R et al. “Adipose cell hyperplasia
and enhanced glucose disposal in transgenic mice
overexpressing GLUT4 selectively in adipose
tissue.” The Journal of biological chemistry vol.
268,30 (1993): 22243-6.

21. Favaretto, Francesca et al. “GLUT4 defects in
adipose tissue are early signs of metabolic

alterations in Alms1GT/GT, a mouse model for
obesity and insulin resistance.” PloS one vol. 9,10
e109540. 9 Oct. 2014,
doi:10.1371/journal.pone.0109540

22. Hubbard, S R, and J H Till. “Protein tyrosine
kinase structure and function.” Annual review of
biochemistry vol. 69 (2000): 373-98.
doi:10.1146/annurev.biochem.69.1.373

23. Lemmon, Mark A, and Joseph Schlessinger.
“Cell signaling by receptor tyrosine kinases.” Cell
vol. 141,7 (2010): 1117-34.
doi:10.1016/j.cell.2010.06.011

24. FDA Fact Sheet, Panitumumab use.
https://www.accessdata.fda.gov/drugsatfda_docs/
label/2009/125147s080lbl.pdf

25. Zhen, Y et al. “Knockdown of EGFR inhibits
growth and invasion of gastric cancer cells.”
Cancer gene therapy vol. 21,11 (2014): 491-7.
doi:10.1038/cgt.2014.55

26. Clinicaltrial.gov, searching criteria
Panitumumab.
https://www.clinicaltrials.gov/ct2/results?cond=P
anitumumab&term=&cntry=US&state=&city=
&dist=&Search=Search

27. Ocaña, Mª Carmen et al. “Fasentin
diminishes endothelial cell proliferation,
di�erentiation and invasion in a glucose
metabolism-independent manner.” Scienti�c
reports vol. 10,1 6132. 9 Apr. 2020,
doi:10.1038/s41598-020-63232-z

28. Chou, Ping‐Chieh, et al. “Impact of Diabetes
on Promoting the Growth of Breast Cancer.”
Cancer Communications, vol. 41, no. 5, 2021,
doi:10.1002/cac2.12147.
doi:https://doi.org/10.1016/j.ejphar.2018.11.028

Berkeley Pharma Tech Journal of Medicine | 116



29. Kraus D, Reckenbeil J, Veit N, et al. Targeting
glucose transport and the NAD pathway in
tumor cells with STF-31: a re-evaluation. Cell
Oncol (Dordr). 2018;41(5):485-494.
doi:10.1007/s13402-018-0385-5

30. Wood TE, Dalili S, Simpson CD, et al. A
novel inhibitor of glucose uptake sensitizes cells to
FAS-induced cell death. Mol Cancer Ther.
2008;7(11):3546-3555.
doi:10.1158/1535-7163.MCT-08-0569

31. Zakikhani, Mahvash, et al. “Metformin Is an
AMP Kinase–Dependent Growth Inhibitor for
Breast Cancer Cells.” Cancer Research, vol. 66,
no. 21, 2006, pp. 10269–10273.,
doi:10.1158/0008-5472.can-06-1500.

32. Dhopeshwarkar A, Mackie K. CB2
Cannabinoid receptors as a therapeutic
target-what does the future hold?. Mol
Pharmacol. 2014;86(4):430-437.
doi:10.1124/mol.114.094649

33. Dowling, Ryan J.O., et al. “Metformin
Inhibits Mammalian Target of
Rapamycin–Dependent Translation Initiation in
Breast Cancer Cells.” Cancer Research, vol. 67,
no. 22, 2007, pp. 10804–10812.,
doi:10.1158/0008-5472.can-07-2310.

34. Apr 25, 2019. (n.d.). Novel MCT4 inhibitors
and uses thereof. Justia. Retrieved April 8, 2023,
from
https://patents.justia.com/patent/20190352282

35. Ben Sahra I., Laurent K., Giuliano S., Larbret
F., Ponzio G., Gounon P., Le Marchand-Brustel
Y., Giorgetti-Peraldi S., Cormont M., Bertolotto
C. Targeting cancer cell metabolism: the
combination of metformin and 2-deoxyglucose
induces p53-dependent apoptosis in prostate

cancer cells. Cancer Res. 2010;70:2465–2475. –
PubMed

36. Chou PC, Choi HH, Huang Y, et al. Impact
of diabetes on promoting the growth of breast
cancer. Cancer Commun (Lond).
2021;41(5):414-431. doi:10.1002/cac2.12147

37. Goodwin PJ, Chen BE, Gelmon KA, et al.
E�ect of Metformin vs Placebo on Invasive
Disease-Free Survival in Patients With Breast
Cancer: TheMA.32 Randomized Clinical Trial.
JAMA. 2022;327(20):1963-1973.
doi:10.1001/jama.2022.6147

38. Au Yeung SL, Luo S, Schooling CM. The
impact of GDF-15, a biomarker for metformin,
on the risk of coronary artery disease, breast and
colorectal cancer, and type 2 diabetes and
metabolic traits: a Mendelian randomisation
study. Diabetologia. 2019;62(9):1638-1646.
doi:10.1007/s00125-019-4913-2

39. Lee SH, Hwang HK, LeeWJ, Kang CM.
MCT4 as a potential therapeutic target to augment
gemcitabine chemosensitivity in resected pancreatic
cancer. Cell Oncol (Dordr). 2021;44(6):1363-1371.
doi:10.1007/s13402-021-00643-8Chou PC, Choi
HH, Huang Y, et al. Impact of diabetes on
promoting the growth of breast cancer. Cancer
Commun (Lond). 2021;41(5):414-431.
doi:10.1002/cac2.12147

40.Goldberg FW, Kettle JG, Lamont GM, et al.
Discovery of Clinical Candidate AZD0095, a
Selective Inhibitor ofMonocarboxylate Transporter
4 (MCT4) for Oncology. J Med Chem.
2023;66(1):384-397.
doi:10.1021/acs.jmedchem.2c01342

41. Lord SR, ChengWC, Liu D, et al. Integrated
Pharmacodynamic Analysis Identi�es Two

Berkeley Pharma Tech Journal of Medicine | 117



Metabolic Adaption Pathways to Metformin in
Breast Cancer. Cell Metab.
2018;28(5):679-688.e4.
doi:10.1016/j.cmet.2018.08.021

42. Birsoy K., Wang T., ChenW.W., Freinkman
E., Abu-RemailehM., Sabatini D.M. An essential
role of the mitochondrial electron transport chain
in cell proliferation is to enable aspartate
synthesis. Cell. 2015;162:540–551. - PMC -
PubMed

43. U.S. National Library of Medicine. (n.d.).
Integrated pharmacodynamic analysis identifies
two metabolic adaption pathways to metformin in
breast cancer.Cell metabolism. Retrieved April 8,
2023, from
https://pubmed.ncbi.nlm.nih.gov/30244975/

44. 44. Anders S., Huber W. Di�erential
expression analysis for sequence count data.
Genome Biol. 2010;11:R106. - PMC - PubMed

45. Memmott, ReganM., et al. “Metformin
Prevents Tobacco Carcinogen–Induced Lung
Tumorigenesis.” Cancer Prevention Research,
vol. 3, no. 9, 2010, pp. 1066–1076.,
doi:10.1158/1940-6207.capr-10-0055.

46. Wilson PM, Yang D, AzumaM, et al.
Intratumoral expression pro�ling of genes
involved in angiogenesis in colorectal cancer
patients treated with chemotherapy plus the
VEGFR inhibitor PTK787/ZK 222584
(vatalanib). Pharmacogenomics J.
2013;13(5):410-416. doi:10.1038/tpj.2012.23

47. Dowling RJ, Zakikhani M, Fantus IG, Pollak
M, Sonenberg N. Metformin inhibits mammalian
target of rapamycin-dependent translation
initiation in breast cancer cells. Cancer Res.
2007;67(22):10804-10812.

doi:10.1158/0008-5472.CAN-07-2310

48. Vernieri C, Signorelli D, Galli G, et al.
Exploiting FAsting-mimicking Diet and
MEtformin to Improve the E�cacy of
Platinum-pemetrexed Chemotherapy in
Advanced LKB1-inactivated Lung
Adenocarcinoma: The FAME Trial. Clin Lung
Cancer. 2019;20(3):e413-e417.
doi:10.1016/j.cllc.2018.12.011

49. Marinello PC, da Silva TN, Panis C, et al.
Mechanism of metformin action inMCF-7 and
MDA-MB-231 human breast cancer cells involves
oxidative stress generation, DNA damage, and
transforming growth factor β1 induction.
Tumour Biol. 2016;37(4):5337-5346.
doi:10.1007/s13277-015-4395-x

50. Gilad Y, Gellerman G, Lonard DM, O'Malley
BW. Drug Combination in Cancer
Treatment-From Cocktails to Conjugated
Combinations. Cancers (Basel). 2021;13(4):669.
Published 2021 Feb 7.
doi:10.3390/cancers13040669

Berkeley Pharma Tech Journal of Medicine | 118




