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Review
. 2022 May 18;14(10):2486.
doi: 10.3390/cancers14102486.

Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review

Tomas Koltai  1 , Stephan Joel Reshkin  2 , Tiago M A Carvalho  2 , Daria Di Molfetta  2 , Maria Raffaella Greco  2 , Khalid Omer Alfarouk  3   4 , Rosa Angela Cardone  2
Affiliations
Review

Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review

Tomas Koltai et al. Cancers (Basel). .

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.

Keywords: desmoplastic reaction; gemcitabine; hydroxyurea; pancreatic ductal adenocarcinoma; proteasome inhibitors; resistance to treatment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Diagram showing the possible mechanism leading to the desmoplastic reaction. It can betriggered by a pancreatic tumor or chronic pancreatitis. The physiopathology of the process seems similar in pancreatic cancer and chronic pancreatitis. Furthermore, non-active stellate cells can be activated through pancreatic injury, thereby becoming the multi-stellate cells that express alpha-smooth muscle actin (that is the reason they are considered myofibroblasts) [213].
Figure 7
Figure 7
Difluorodeoxyuridine exerts inhibitory effects on cytidine deaminase, thus increasing gemcitabine’s intracellular effects, and it competitively antagonizes gemcitabine intake through hENT. A lower activity of cytidine deaminase is paralleled by a higher cytotoxicity of gemcitabine. This diagram is based on references [248,249,252,253,254,255]. The figure also shows that both gemcitabine and its metabolite difluorodeoxyuridine have the ability to inhibit thymidylate synthase (TS), with further toxicity [256,257]. TS inhibition by 5-FU increased gemcitabine sensitivity [258,259]. Tymidylate synthase inhibition seems to be a valid alternative to gemcitabine in PDAC [260,261].
Figure 2
Figure 2
Gemcitabine chemical formula [222] on the left side. The right side shows 2-deoxycytidine (cytosine deoxyribonucleoside), the nucleosidewhich gemcitabine competes against. Cytosine deoxyribonucleoside is one of the four nucleosides that form part of DNA.
Figure 3
Figure 3
Mechanism of gemcitabine’s access to the cell. Gemcitabine membrane transporters.
Figure 4
Figure 4
Gemcitabine’s first intracellular phosphorylation by deoxycytidine kinase.
Figure 5
Figure 5
Second and third phosphorylations of gemcitabine by the nucleoside monophosphate kinase and nucleoside diphosphate kinase respectively, rendering the active form: difluoro deoxycytidine.
Figure 6
Figure 6
The mechanism of action of gemcitabine is by competing with deoxycytidine. Incorporation of gemcitabine into the DNA strand introduces an irreparable error that the cell cannot circumvent. This faulty DNA unleashes apoptotic mechanisms. A high level of deoxycytidine may prevail over gemcitabine, reducing its effects. The DNA synthesis mechanism is over-simplified in the diagram, the objective of which is to show how an increased glycolytic flux participates in resistance to gemcitabine. Lonidamine, which significantly decreases glycolysis, is probably good to associate with gemcitabine to prevent resistance, although this has not been tested. Increased expression of ribonucleotide reductase, specifically the M1 isoform, is also an important participant in resistance.
Figure 8
Figure 8
The two pathways shown in the figure have been found to decrease gemcitabine’s cytotoxity and apoptosis. SDF-1α expression is induced by galectin 1.
Figure 9
Figure 9
The two mechanisms involved in treatment resistance induced by oncomucins. This diagram is based on references [330,331,332,333,334,335,336,337,338,339,340,341,342,343].
Figure 10
Figure 10
The yellow squares are the known activators of pancreatic cancer stem cells. The other activators (white squares) have also been found to play a role. This diagram is based on references [382,383,384,385,386,387,388,389,390,391,392,393,394,395,396,397,398,399,400,401]. Importantly, many of the stemness activators are also involved in epithelial–mesenchymal transition.
Figure 11
Figure 11
Mechanism of hypoxia-inducedgemcitabine resistance.
Figure 12
Figure 12
Some mechanisms of resistance to gemcitabine in PDAC. ABC: ATP binding cassette. Poor vascular supply and the desmoplastic reactionare mainly physical barriers. The numbers are chemicals and pathways activated for the escape. ABC re-exports the cytotoxic substances.
Figure 13
Figure 13
Gemcitabine increases IL-6 expression in the surviving malignant cells, which in turn inhibits gemcitabine’s cytotoxicity through the production/secretion of IL-6.
Figure 14
Figure 14
Basedoxifene inhibits GP-130 which is precisely the starting point of IL-6signaling.
Figure 15
Figure 15
Other pathways that participate in gemcitabine resistance. This diagram is based on references [548,549,550,551,552,553,554,555,556,557,558,559,560].
Figure 16
Figure 16
Factors influencing exosome formation and actions. Black arrows show mechanisms that increase exosome production, and red arrows the protumoral effects of these exosomes.
Figure 17
Figure 17
A possible scheme for multi-targeting PDAC to prevent/reverse chemoresistance. A rational association of drugs will probably enhance gemcitabine anti-cancer effects and reduce resistance. The drugs proposed to be associated with gemcitabine have low or no toxicity at all and would not represent an extra burden for the patient. Furthermore, amiloride and tocilizumab may prevent cancer cachexia [603,604], a frequent occurrence in PDAC.
Figure 18
Figure 18
Role of DNA double-strand break-repair proteins in gemcitabine’s cytotoxicity.
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