Targeting AML Growth: Vitamins' Influence on FLT3, NPM1, and RUNX1 Interactions

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Targeting AML Growth: Vitamins' Influence on FLT3, NPM1, and RUNX1 Interactions

https://doi.org/10.21203/rs.3.rs-3799347/v1

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The call for implementing inhibitory methods in cancer treatment has intensified. Recently, cancer has deeply affected society, with Acute Myeloid Leukemia (AML) being identified as one of the most formidable and lethal adversaries. This research investigates the intricate interactions between vitamins A, B, C, D, E, and K and critical signaling pathways, such as NPM1, FLT3, and RUNX1, uncovering meaningful associations. Employing the precision of molecular docking with Autodock Vina 1.5.7, a thorough exploration of these interactions was carried out. The analysis entailed a detailed examination of hydrophilic and hydrophobic aspects using LigPlot, complemented by additional insights visualized through PyMol. The considerable occurrence of observed hydrophilic interactions, coupled with the noteworthy binding energy, underscores the potential of vitamin-related derivatives as promising contenders for inhibitory cancer treatments. However, the realization of this potential is contingent upon subsequent investigations, including a comprehensive exploration through RT-qPCR studies. While the study has successfully identified significant interactions, the intricate dynamics of gene expression necessitate thorough studies to attain a holistic understanding of both upregulation and downregulation. In conclusion, the revelations from this study not only set the stage for potential inhibitory treatments of AML through the strategic application of vitamin-based derivatives but also underscore the transformative capabilities of these derivatives. In future research endeavors, should vitamin interactions reveal substantial downregulation, these derivatives stand poised to spearhead innovative cancer treatments, marking a transformative era in targeted drug delivery.

One of the significant challenges confronting the field of biomedical engineering today is the effective treatment of cancers. According to a 2020 report, there were an estimated 19.3 million new cancer cases worldwide, with 10.0 million resulting in fatalities [1]. This global prevalence underscores that approximately 52 percent of cases lead to death if not addressed promptly [2]. Leukemia, a relatively uncommon form of cancer, originates from the body's blood-forming tissues, including the bone marrow and the lymphatic system [3]. This type of cancer triggers the metastasis of white blood cells, impairing the human immune system [4]. Due to the compromised immune system and the spread of blood cells, the 5-year relative survival rate for individuals aged 20 and older with Acute Myeloid Leukemia (AML) is only 28%. [5] Despite chemotherapy being the standard treatment for AML, it comes with the drawback of damaging white blood cells, resulting in a weakened immune system and severe consequences [6]. Hence, the quest for an alternative inhibitory treatment method persists—one that can mitigate the severity of cancer without causing harm to the surrounding cells.

Vitamins, indispensable elements vital for proper metabolism, have evolved beyond their fundamental role and emerged as therapeutic agents, particularly for regenerative applications [7, 8]. The utilization of vitamins in therapeutic contexts stems not only from their medicinal efficacy but also from their relatively lesser-known side effects [9–12]. In contemporary medicinal research, vitamins and their derivatives have garnered substantial attention as promising candidates for cancer-related treatments [13]. Recent studies highlight the pivotal role of vitamin D in impeding the growth of sarcomas [14]. Additionally, investigations reveal that intravenous release of vitamin C can ameliorate the treatment of ovarian cancers [15]. Controlled delivery of retinoids or vitamin A derivatives has shown promise in diminishing the risk of inducing carcinoma in the stomach [16]. The University of Chicago underscores that the release of retinol derivatives can enhance the efficacy of chemotherapy, expediting recovery [17]. Extensive research on vitamin K, a well-established therapeutic agent, indicates its inhibitory effects on cancer growth [18]. Furthermore, recent findings associate vitamin K intake with a reverse correlation to cancer incidence and mortality [19]. Despite the extensive exploration of vitamins and their derivatives in cancer treatment, the impact of vitamin release on AML remains inadequately investigated.

NPM1, or nucleophosmin 1, plays a significant role in the context of AML. NPM1 is a gene that encodes for a nucleolar phosphoprotein involved in various cellular functions, including ribosome biogenesis and centrosome duplication [20]. In AML, NPM1 mutations are one of the most common genetic alterations, particularly in cases with normal cytogenetics [21]. The presence of NPM1 mutations in AML has important diagnostic and prognostic implications [22]. In fact, NPM1 mutations have been incorporated into the World Health Organization (WHO) classification criteria for AML [23]. Typically, these mutations involve the cytoplasmic displacement of the NPM1 protein, leading to its accumulation in the cytoplasm rather than its usual localization in the nucleolus [24]. The detection of NPM1 mutations has become a valuable tool in the diagnostic workup of AML [25]. From a prognostic perspective, AML patients with NPM1 mutations, especially those without concurrent FLT3-ITD (FMS-like tyrosine kinase 3 - internal tandem duplication) mutations, are considered to have a more favorable prognosis. This subset of AML patients often responds well to standard chemotherapy and exhibits a higher likelihood of achieving complete remission. Furthermore, the understanding of the molecular mechanisms underlying NPM1-mutated AML is driving targeted therapeutic research [26, 27]. Efforts are underway to develop treatments that specifically address the unique biology associated with NPM1 mutations, offering more tailored and effective interventions for individuals with AML harboring these genetic alterations.

Another crucial protein in the context of AML is FLT3, playing a significant role. FLT3, or FMS-like tyrosine kinase 3, holds considerable significance in the context of AML [28]. It is a receptor tyrosine kinase that plays a pivotal role in regulating the growth and differentiation of hematopoietic cells [29]. In AML, FLT3 mutations are among the most frequent genetic alterations. Mutations in the FLT3 gene, particularly internal tandem duplications (FLT3-ITD), lead to constitutive activation of the FLT3 receptor, resulting in uncontrolled cell proliferation and resistance to apoptosis [30]. The presence of FLT3 mutations is associated with adverse prognostic implications in AML, indicating a higher risk of relapse and poorer overall survival. Due to its prominence in AML pathogenesis, FLT3 has become a key target for therapeutic interventions [31]. Several FLT3 inhibitors have been developed and are actively being investigated in clinical trials. These inhibitors aim to counteract the aberrant signaling pathways triggered by FLT3 mutations, thereby hindering the growth and survival of leukemia cells [32]. The integration of FLT3 mutational status into the risk stratification of AML patients has become essential for treatment decision-making [33]. The identification of FLT3 mutations not only informs prognosis but also guides the selection of targeted therapies, fostering a more personalized and effective approach to managing AML [34]. Ongoing research continues to deepen our understanding of FLT3 and explore innovative strategies to target this protein for improved outcomes in AML patients.

RUNX1, also known as runt-related transcription factor 1, plays a critical role in the context of AML [35]. It is a transcription factor that contributes to the regulation of normal hematopoiesis by controlling the development and function of blood cells. In AML, the RUNX1 gene is frequently disrupted by mutations or chromosomal translocations, leading to the formation of abnormal fusion proteins [36]. These genetic alterations often result in dysfunctional RUNX1 activity, impairing its ability to regulate gene expression properly [37]. The aberrant function of RUNX1 contributes to the development and progression of AML by promoting uncontrolled cell proliferation and inhibiting the normal maturation of blood cells [38]. RUNX1 mutations are commonly associated with specific subtypes of AML and are considered significant prognostic indicators [39]. AML patients with RUNX1 mutations may exhibit distinct clinical and biological characteristics, influencing disease outcomes and treatment responses [40]. The identification of RUNX1 mutations has become an integral part of the molecular profiling of AML, aiding in risk stratification and treatment decision-making [41]. The evolving understanding of the molecular mechanisms involving RUNX1 in AML has also paved the way for the exploration of targeted therapies that aim to restore normal RUNX1 function or mitigate the effects of its aberrant activity [42].

Ayurveda, an ancient Indian medicinal system with a rich historical legacy, has been harnessed for centuries to address a spectrum of health conditions [43]. This time-honored approach to healing is deeply entrenched in the utilization of natural sources. Despite the scientific discovery of vitamins in the 20th century, their roots extend back to ancient India, where their natural origins were tapped into for addressing various health concerns. The exploration of whether vitamins could potentially alleviate the challenges posed by AML raises critical questions. Can we actively pursue inhibitory treatments for this profoundly lethal form of cancer? In the pursuit of answers, computational simulations have been meticulously conducted. These simulations delve into the intricate interactions between vitamins and diverse gene expressions, with the overarching goal of hindering the growth of AML. This research endeavors not only to enhance our understanding of potential therapeutic avenues but also to contribute significantly to a future marked by improved health and a reduction in the prevalence of cancer.

In our study, we investigated the docking interactions between four ligands and proteins. Specifically, the ligands chosen for the docking analysis comprised Vitamin A, Vitamin B-12, Vitamin C, Vitamin D-3, Vitamin E, and Vitamin K. Each ligand underwent individual docking analyses with three distinct proteins: NPM1 (8AS5), FLT3 (1RJB), and RUNX1 (1EAQ). The structures of both the vitamins and proteins were obtained from PubChem and the RSCB databases in PDB format. Subsequently, these structures underwent molecular docking using Autodock Vina 1.5.7 software. The resulting interactions were then visualized and analyzed using Pymol, and Ligplot was employed to depict the polar interactions between the proteins and ligands.

2.1 Molecular Docking

Molecular docking is a computational technique widely used in the field of bioinformatics and drug discovery to predict and analyze the binding interactions between small molecules (ligands) and target macromolecules (usually proteins) [44]. The primary objective of molecular docking is to simulate and evaluate the most energetically favorable binding configurations between a ligand and a protein, providing insights into the potential strength and nature of the binding. In the context of drug discovery, molecular docking serves as a crucial tool for screening and identifying potential drug candidates [45]. The process involves predicting the spatial arrangement of a ligand within the binding site of a target protein, assessing the binding affinity, and estimating the overall stability of the complex. This information is valuable in selecting lead compounds for further experimental validation and optimization. Molecular docking algorithms utilize scoring functions to rank different binding conformations, considering factors such as hydrogen bonding, van der Waals forces, electrostatic interactions, and desolvation energies. Various software tools, such as Autodock, Glide, and GOLD, have been developed to facilitate molecular docking studies, offering researchers user-friendly interfaces and efficient algorithms for accurate predictions. The applications of molecular docking extend beyond drug discovery to fields such as structural biology, where it aids in understanding protein-ligand interactions, and in the study of biomolecular dynamics. Overall, molecular docking has become an indispensable tool for exploring the molecular basis of biological processes and accelerating the identification of potential therapeutic agents [46].

The optimal protein-ligand docked conformation is characterized by the ligand being strategically positioned to exhibit the least binding energy with the target protein. The lower the binding energy, the greater the stability of the protein-ligand complex, making binding free energy a critical parameter in molecular docking studies. In this investigation, Autodock tools were employed to prepare ligands and protein structures, and AutoDock Vina 1.5.7 was utilized for docking analysis [47, 48]. Autodock Vina facilitates the preparation of protein molecules by generating a PBDQT File with the appropriate 3D structure, eliminating water, and introducing polar hydrogen and Kollman charges. The Autogrid method establishes a 3D grid around the binding site of the target, defining the search space for placing the small molecule. Blind docking is conducted with a cubical box of X Å sides and a grid spacing of 0.375 Å, centered at the proteins' central locations in each case. Ten well-suited configurations are generated using an exhaustiveness factor of 9, and the highest scored docked configuration based on binding affinity is further examined in this study. The investigation delves into expected binding postures by considering hydrogen bonding patterns and other interactions.

3.1 Hydrophilic and hydrophobic interactions

3.1.1 Interactions of vitamins with FLT3

Vitamin A or retinol in general showed hydrophobic interactions with the specific site and lack of hydrophilic interaction was observed in the region of highest docking score. On the contrary, vitamin C showed very high hydrophilic interactions with FLT3. Interactions were observed with residual chains Ala657 (A), Val592 (A) and Ser574 (A). Vitamin D, E and K also showed negligible hydrophilic interactions most of the interactions observed were hydrophobic ones. The interactions are showed in Fig. 3.

3.1.2. Interactions of vitamins with NPM1

Vitamin A had mostly hydrophobic interactions, however some hydrophilic interactions were observed in the site of docking. Residual chain Ser70(E) showed hydrophilic interactions with the ligand. Similar to the interactions with FLT3, Vitamin C showed very high interaction with NPM1. Residual chains Ser88(A), Ser88(E), SER88(E), Ser88(D) showed significanly high hydrogen bonding ability. Vitamin D showed mostly hydrophobic interactions. Vitamin E showed hydrophilic intereaction with residual chain Leu18(A). Other interactions were mostly hydrophobic interactions. Similar results were observed for vitamin K. Residual chain Tyr29(A) showed hydrophilic interaction and hydrogen bonding ability with vitamin K. The interaction is provided in Fig. 5.

3.1.3. Interactions of vitamins with RUNX1

Figure 4 depicts that Vitamin A showed mostly hydrophobic intreactions with RUNX1. Vitamin C had mostly hydrophilic interactions and which are desirable. The interactions of vitamin C were with Gly141(B), Lys167(B), Ser140(A) and Glu111(A). Vitamin D had mostly hydrophobic interactions. However, some hydrophilic interactions were also visible. Glu111(A) is one such residual chain where hydrophilic interactions were observed. Vitamin E had both hydrophilic and hydrophobic interactions. Lys167(B) chain and Glu111(A) had hydrophilic interactions.

3.2. Molecular docking

In this study, molecular docking was conducted using Autodock Vina. The blind binding affinity of vitamin A with FLT3 was determined to be -4.4 kcal/mol, with a more favorable binding affinity of -5.1 kcal/mol observed with NPM1. However, the affinity decreased with interactions with RUNX1, reaching − 4.7 kcal/mol. Vitamin C exhibited intriguing interactions, displaying a binding affinity of -6.2 kcal/mol with FLT3 and excellent affinities of -6.0 kcal/mol and − 4.9 kcal/mol with NPM1 and RUNX1, respectively, attributed to extensive hydrogen bonding with the residual chains. Vitamin D, despite minimal hydrogen bonding, demonstrated notable affinity values of -6.1 kcal/mol, possibly due to other physical interactions such as van der Waals, LJ, Tersoff potential, or other chemical interactions. Vitamin D also exhibited relatively strong interactions with NPM1 and RUNX1, with affinity values of -5.2 kcal/mol and − 5.4 kcal/mol, respectively. Similarly, vitamin E displayed a favorable docking score of -5.7 kcal/mol with FLT3, along with relatively good scores of -6.0 kcal/mol and − 4.6 kcal/mol with NPM1 and RUNX1. Vitamin K yielded a binding affinity of -4.8 kcal/mol with FLT3, a higher affinity of -6.6 kcal/mol with NPM1, and a comparatively lower value of -3.9 kcal/mol with RUNX1.

AML represents a malignancy stemming from aberrant white blood cells, integral components of the immune system [37]. The occurrence of dysregulation or abnormalities in key signaling pathways, such as NPM1, FLT3, and RUNX1, is closely linked to the development of AML [49, 50]. These intricate pathways play pivotal roles in the regulation of cell proliferation, and mutations within them can significantly contribute to the unbridled proliferation or metastasis characteristic of AML. A comprehensive understanding of these signaling pathways not only sheds light on the underlying molecular mechanisms but also unveils potential targets for therapeutic intervention. In this particular study, we delve into the intricate interplay between vitamins and the proteins within these critical signaling pathways, seeking to elucidate whether vitamin molecules possess the capacity to modulate the expression of these proteins. The visual representation in Fig. 1 intricately illustrates the mechanistic impact of vitamins on diverse gene expressions, offering valuable insights into the genesis of AML.

Recently, vitamins have emerged as pivotal players in the realm of medicinal chemistry [51]. Notably, vitamin A has demonstrated the capability to impede the growth of sarcoma, unveiling a promising avenue for therapeutic interventions [52]. Studies have further indicated the potential therapeutic efficacy of vitamins C, D, E, and K in combating a spectrum of malignancies [53–57]. Despite these advancements, the impact of vitamins on the proliferation of AML remains insufficiently explored. In this study, we endeavored to unravel the intricate interactions between vitamins and different signaling pathways. Employing molecular docking techniques, we delved into the complex world of protein-vitamin interactions. This exploration encompassed a spectrum of molecular forces, including hydrophilic and hydrophobic interactions, LJ potential, Tersoff potential, Kollman charges, pi-pi, and van der Waals interactions. Our comprehensive investigation seeks to unveil the potential of vitamins in influencing AML proliferation, providing a deeper understanding of the molecular dynamics at play.

Utilizing AutoDock Vina 5.0, we conducted sophisticated simulations involving the molecular docking of Vitamins A, C, D, E, and K with molecules integral to signaling pathways. Our meticulous analysis pinpointed nine potential docking cases, with the foremost case exhibiting the least binding energy and the highest degree of promise. Scrutinizing the molecular structure of the docked complex unveiled the intricate influence of various factors on hydrogen bonding and binding energy, including Kollman Charges, Van der Waal’s forces, Pi-Pi interactions, LJ Potential, and Tersoff Potential. Detailed depictions of interactions occurring below the 4.0 Å threshold are eloquently illustrated in Figs. 3–6, contributing substantively to the comprehensive understanding of the overall binding energy in the context of our molecular docking simulations.

Our simulation compellingly indicates that vitamins exhibit robust interactions with proteins, suggesting a substantial potential to influence their upregulation or downregulation. This pivotal discovery of interactions within diverse signaling pathways marks a crucial advancement in the pursuit of life-saving treatments for AML, leveraging vitamin-based therapeutic drug delivery strategies. The imperative next steps involve further research and conducting RT-qPCR tests to meticulously examine the impact of these interactions on gene expressions. Should the interactions with vitamins demonstrate significant downregulation, it could signify a groundbreaking pathway for alternative cancer treatments, illuminating a promising and transformative trajectory for the future of cancer therapeutics.

This study delves into the intricate interactions between vitamins (A, B, C, D, E, and K) and various pivotal signaling pathways, including NPM1, FLT3, and RUNX1, unveiling noteworthy associations. Employing the precision of molecular docking with Autodock Vina 1.5.7, we meticulously scrutinized these interactions, subjecting them to in-depth analysis for hydrophilic and hydrophobic aspects using LigPlot. Further insights were gleaned through comprehensive examination and visualization of additional interactions employing PyMol. The substantial number of observed hydrophilic interactions coupled with significant binding energy underscores the potential of vitamin-related derivatives as promising candidates for inhibitory cancer treatments. This consideration is, however, contingent upon subsequent investigations, including detailed RT-qPCR studies. While significant interactions have been pinpointed, the complexity of gene expression dynamics necessitates thorough studies and experiments for a comprehensive understanding of both upregulation and downregulation. In summation, the discoveries in this study pave the way for potential inhibitory treatments of AML through the strategic utilization of vitamin-based derivatives. In future research endeavors, if vitamin interactions manifest substantial downregulation through significant interactions, vitamins and their derivatives stand poised to spearhead innovative cancer treatments, heralding a transformative era in targeted drug delivery.

1. Ethics approval and consent to participate: The work is ethically correct and all the authors consent to participate.

2. Consent for publication: The authors give the consent to publish the article.

3. Competing interests: There is no competing interests.

4. Funding: Not applicable.

5. Authors’ contribution:

1. Tunnisha Dasgupta: Preparation of original draft, Visualization, Data procurement and data analysis.

2. Rounak Chatterjee: Preparation of original draft, Visualization, Data procurement and data analysis.

3. Moumita Mondal: Preparation of original draft, Visualization, Data procurement and data analysis.

4. Soham Sen: Preparation of original draft, Visualization, Data procurement and data analysis.

5. Soumil Banik: Preparation of original draft, Visualization, Data procurement and data analysis.

6. Subhadeep Pati: Preparation of original draft, Visualization, Data procurement and data analysis.

7. Gora Chand Chell: Preparation of original draft and data analysis.

8. Sikta Mondal: Preparation of original draft and data analysis.

9. Saptaparna Sen: Preparation of original draft and data analysis.

10. Yongdeok Jo: Conceptuaization, Preparation of original draft, Visualization, Data procurement and data analysis.

11. Ujjayan Majumdar: Conceptualization, Preparation of original draft, Visualization, Data procurement and data analysis.

6. Acknowledgement: We want to acknowledge Uday Majumder, for his guidance with molecular biology.

Conflict of interest

The authors declare that there is no conflict of interest.

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The authors declare no competing interests.

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Targeting AML Growth: Vitamins' Influence on FLT3, NPM1, and RUNX1 Interactions

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Abstract

Figures

1. Introduction

2. Materials and methods

2.1 Molecular Docking

3. Results

3.1 Hydrophilic and hydrophobic interactions

3.1.1 Interactions of vitamins with FLT3

3.1.2. Interactions of vitamins with NPM1

3.1.3. Interactions of vitamins with RUNX1

3.2. Molecular docking

4. Discussion

5. Conclusion

Declarations

References

Additional Declarations

Supplementary Files

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