Resveratrol and pancreatic cancers: Questions and future perspectives

Abstract

There is still no effective treatment for pancreatic cancer, one of the deadliest malignancies among the gastrointestinal diseases. Jiang et al demonstrated the presence of senescent cancer-associated fibroblasts (CAFs) in pancreatic cancer tissues, supporting the use of CAFs as potential anti-cancer targets. The study indicated that a natural plant-derived compound resveratrol can reverse senescent CAF phenotype and decrease the growth, migration, and invasiveness of pancreatic cancer cells. Notably, the study indicated that resveratrol might be involved in regulating epithelial-to-mesenchymal transition in the tumor microenvironment. This editorial shares insights on the future investigation of resveratrol signaling in cancer cells and the tumor microenvironment, and discusses resveratrol-based treatment perspectives.

Key Words: Pancreatic cancer; Resveratrol; Cancer-associated fibroblasts; Tumor microenvironment; Antioxidant; Immune senescence

Core Tip: A promising new direction for the treatment of pancreatic cancer has been investigated and reported by Jiang et al. Using immunohistochemistry, the authors assessed pancreatic cancer tissues and detected the presence of senescent cancer-associated fibroblasts (CAFs) in the tumor microenvironment. Following this, the authors observed the ability of the natural polyphenolic compound resveratrol to reverse the senescent CAF phenotype and inhibit pancreatic cancer progression in vitro and in vivo. This editorial assesses important aspects of the original article and discusses future perspectives of resveratrol-containing therapy.

INTRODUCTION

Resveratrol, a natural polyphenolic compound (stilbenoid, phytoalexin) detected in various fruits and vegetables, has been reported as a highly promising agent with anti-cancer and autophagy-promoting properties. The agent was indicated to be an important nutraceutical which positively regulates functions of the gut microbiome and impacts overall metabolism[1,2]. The unique antioxidant and anti-inflammatory properties of resveratrol signify its cancer-preventing properties[2].

Resveratrol demonstrated numerous beneficial effects. Inhibition of proliferation and activation of apoptosis were reported in malignant cells treated with resveratrol[3,4]. Jiang et al[5] reported several anti-cancer effects of resveratrol in pancreatic cancer. The interesting findings in this study include the identification of senescent cancer-associated fibroblasts (CAFs) in pancreatic cancer tissues and the association of CAF abundance with cancer progression. Senescent CAFs, as part of the tumor microenvironment (TME), were shown to promote cancer progression in many recent investigations, although only a few reports were related to pancreatic cancers. We aim to assess several important aspects of the novel study by Jiang et al[5] and provide our own insight into the future clinical applications of resveratrol.

PANCREATIC CANCER-ASSOCIATED TARGETS FOR RESVERATROL: NEXT STEPS

The evidence-based strength of the study by Jiang et al[5] is associated with the use of human tissue samples and histological analysis. Immunohistochemistry provided a visual identification of CAFs in pancreatic tumors, suggesting a potential application of this method in diagnostics, although further studies with larger populations are warranted. The use of fluorescent microscopy also provided a reliable visual confirmation of resveratrol-induced inhibition of the senescent CAF phenotype. Resveratrol blocked the expression of senescent indicators p16 and alpha smooth muscle actin, confirming a genome-based effect of resveratrol in these cells. The authors also determined the biological effects of resveratrol using cell proliferation and migration assays in cultured PANC-1 and SW1990 human pancreatic cancer cell lines. This is the first published report on resveratrol effects in SW1990 cells, although other groups observed similar growth-inhibiting effects in PANC-1 and BxPC-3 cells. In vivo experiments with grafting of BxPC-3 cells confirmed resveratrol abilities to impact the CAF phenotype. Thus, the study provides experimental evidence that resveratrol targets TME-located CAFs, a very promising anti-cancer target in pancreatic cancers[6]. Recent ground-breaking findings indicated that senescent CAFs may prevent the immunotherapy-induced activation of cluster of differentiation 8 + T cells subsets and serve as an impediment for pancreatic cancer treatment[6].

It is important to note that resveratrol was shown to influence different effectors and demonstrated complex signaling effects related to cancer elimination. For instance, pleiotropic mechanisms of resveratrol-induced effects were linked to epigenetic modifications[3]. Resveratrol was also shown to induce autophagic cell death[7]. Activated sirtuin 1 (SIRT1) and downregulated signaling of the protein kinase B (AKT)/mammalian target of rapamycin pathways were also associated with the autophagy-inducing effects of resveratrol[7]. Autophagy-activating effectors, such as AKT and SIRT1, can trigger or counteract cell death, accenting the cell- and disease-specific complexity of this pathway. The controversial effects of resveratrol in different cancers may be associated with the diversity of downstream effectors (molecular targets) in a cell-specific manner[2,3,7,8].

Jiang et al[5] found that co-culturing senescent CAFs with pancreatic cancer cells stimulated the proliferation, migration, and invasive capacities of malignant cells. Moreover, the presence of senescent CAF cells in the pancreatic cancer cell culture led to decreased E-cadherin and increased N-cadherin and vimentin expression, which was accompanied by the stimulation of epithelial-mesenchymal transition (EMT). Notably, resveratrol treatment reversed these effects[5]. Resveratrol downregulated the expression of EMT markers (N-cadherin and vimentin) but stimulated the expression of E-cadherin (see Figure 6 from Jiang et al[5]). It would be very interesting to investigate how resveratrol reduces the senescence of CAFs. Suggestively, several downstream effectors can be involved in this process.

For instance, the study did not test the role of sphingosine kinase (SphK) and/or its substrate, sphingosine-1-phosphate (S1P) and S1P receptors. A previous study indicated the abilities of resveratrol to regulate sphingolipid metabolism[8]. Increased expression of SphK1 was reported in CAFs from ovarian cancers[9]. Resveratrol decreased SphK1 activation in leukemia cells[10], skin inflammation models[11] and modulated SphK1 signaling/S1P levels in various normal and cancer cells[12]. Resveratrol dimers (ampelopsin A and balanocarpol) were defined as SphK1 inhibitors, which also downregulated the kinase expression in breast cancer cells[13]. Resveratrol was also shown to decrease cancer cell growth via downregulation of SphK2[14]. A recent study indicated that SphK2 deficiency was associated with lower S1P levels, but increased ceramide content in stromal fibroblasts[15]. Moreover, in SphK2 -/- mice, the deletion of SphK2 enzyme was linked to reduced tumor proliferation/metastasis, immunosuppressive TME, and specifically diminished the CAFs gene signature[15]. Suppressed cancer growth was also observed in the presence of fibroblasts with SphK2 deletion, suggesting the key role of this enzyme in the stimulation of tumor growth by TME/CAFs[12]. Other potential TME targets for pancreatic cancer prevention include specific T cell subsets/natural killer cells, which can also be influenced by modified sphingolipid signaling[16]. Significant increases in the numbers of circulating γδ T cells and regulatory T cells indicated a potential connection between resveratrol and S1P receptor signaling (preclinical studies in humans)[17]. S1P receptors were shown to direct T cell trafficking in multiple studies, as reviewed previously[18]. S1P/SphK pathway signaling is very complex and often leads to anti-apoptotic effects in cancers[13,18], demonstrating the need to clarify the role of this molecular machinery in pancreatic cancer cells treated with resveratrol.

The main challenge for resveratrol application in clinics is associated with the agent’s limited bioavailability (poor solubility) and the necessity to look for advanced drug delivery formulations[19]. One of the first attempts (over a decade ago) to generate bioavailable resveratrol led to clinical trials of micronized resveratrol (SRT501) in colon cancer patients with liver metastases[20]. Interestingly, SRT501 was well tolerated and stimulated apoptosis in the metastatic liver cancer cells[20]. Recent research indicated an optimistic impact of several nano formulations on resveratrol solubility associated with improved anti-cancer effects in vivo[21]. However, the pharmacokinetics and chemotherapeutic benefits of resveratrol warrant further clinical investigations to confirm the safety of the novel nanomedicine. A combined resveratrol-copper formulation (R-Cu) was tested in gastric cancer patients (clinical trial information CTRI/2019/07/020289). The R-Cu formulation reduced the non-hematological toxicity of docetaxel-based multi-agent chemotherapy[22]. Another study indicated that intracellular copper reacted with resveratrol within prostate cancer cells, leading to the generation of reactive oxygen species and DNA damage[23]. However, the role of resveratrol in the activation of cuproptosis (a copper-related type of cell death)[24] remains to be explored.

CONCLUSION

Future studies may aim to unlock the full potential and benefits of resveratrol using advanced delivery techniques, such as liposomes, emulsions, metal ion chelation, and nanoencapsulation. Moreover, it remains to be investigated whether encapsulated/chelated resveratrol[21,24] delivers similar cancer-eliminating effects. The enhanced pharmacokinetics and potential chemotherapeutic benefits of resveratrol should be further tested to confirm the reduced toxicity of the agent applied together with novel therapy, including check-point immunotherapy. Reported observations warrant further investigations and reveal the importance of uncovering the resveratrol interaction with sphingolipid metabolism, oxidative stress, and inflammation in cancer and the TME.