The Indonesian Biomedical Journal.
Vol.
No.
October 2025, p.
Print ISSN: 2085-3297.
Online ISSN: 2355-9179
RESEARCH ARTICLE
Inositol Hexakisphosphate (InsPCI) Induces Apoptosis via Caspase-Dependent Pathways: Molecular Docking Insights Ferry Sandra1,E.
Dewi Ranggaini2.
Johni Halim2.
Alfred Pakpahan3.
Visi Endah Pratitis4.
Kyung Hoon Lee5 Department of Biochemistry and Molecular Biology.
Division of Oral Biology.
Faculty of Dentistry.
Universitas Trisakti.
Jl.
Kyai Tapa No.
Jakarta 11440.
Indonesia Department of Physiology.
Division of Oral Biology.
Faculty of Dentistry.
Universitas Trisakti.
Jl.
Kyai Tapa No.
Jakarta 11440.
Indonesia Department of Oral Biology.
Faculty of Dentistry.
Universitas Trisakti.
Jl.
Kyai Tapa No.
Jakarta 11440.
Indonesia The Prodia Education and Research Institute.
Jl.
Kramat Raya No.
Jakarta 10430.
Indonesia Research Institute.
Ballys Co.
Ltd.
Incheon 22219.
Republic of Korea *Corresponding author.
Email: ferry@trisakti.
Received date: Aug 22, 2025.
Revised date: Sep 22, 2025.
Accepted date: Oct 1, 2025 Abstract ACKGROUND: Inositol hexakisphosphate (InsPCI) exhibits anticancer activity, especially by inducing intrinsic and extrinsic apoptotic pathways.
However, there is still no molecular docking evidence that directly examines InsPCI interactions with either upstream or downstream apoptotic regulators.
Therefore, the current study was conducted to investigate the molecular docking of InsPCI to caspases as upstream/downstream apoptotic regulators.
METHODS: Ligands including InsPCI.
InsPCI.
InsPCE, histone deacetylase inhibitor, and caspase inhibitors were retrieved from PubChem, while target proteins .
istone, caspase-8, caspase-2, and caspase-.
were obtained from the Protein Data Bank.
Ligand toxicity was predicted using ProTox-3.
0, and physicochemical properties were analyzed with SwissADME.
Ligand structures were energy-minimized using PyRx with the Universal Force Field, while proteins were prepared by removing water molecules and non-essential heteroatoms in BIOVIA Discovery Studio.
Molecular docking was conducted using CBDock 2.
0, with binding poses selected based on the lowest Vina score, and ligandAeprotein interactions were visualized in Discovery Studio.
RESULTS: Molecular docking results showed that InsPCI bound strongly to histone, caspase-8, caspase-2, and caspase-3 with affinities comparable to reference inhibitors, forming multiple hydrogen bonds with key active-site residues.
InsPCI.
InsPCI, and InsPCE exhibited several similar binding sites to caspase-3, with only minor differences in binding affinity.
CONCLUSION: InsPCI shows strong binding to histone, caspase-8, caspase-2, and caspase-3 based on in silico results, supporting its role in inducing both extrinsic and intrinsic apoptotic pathways.
Taken together.
InsPCI could be a potential inducer of apoptosis in cancer cells.
KEYWORDS: cancer, apoptosis.
InsPCI.
InsPCI.
InsPCE, caspase, in silico, molecular docking Indones Biomed J.
: 475-83
Introduction Inositol hexakisphosphate (InsPCI) has been identified as a potent anticancer compound by targeting crucial biological pathways.
Recent studies have highlighted anticancer potential of InsPCI, which includes inhibition of cell proliferation, blockade of the cell cycle, and induction of apoptosis.
These effects are linked to its ability to control key signaling pathways and to activate apoptosisrelated proteins.
Therefore.
InsPCI is considered a promising natural agent with potential anticancer activity, particularly Copyright A 2025 The Prodia Education and Research Institute.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.
0 International (CC-BY-NC) License.
DOI: 10.
18585/inabj.
through its role in inducing apoptosis in cancer cells.
The potential of InsPCI has been validated across multiple cancer cell types.
In HeLa cells.
InsPCI inhibits cell growth and induces apoptosis through caspase activation and suppression of the Akt-nuclear factor-kappa B (NF-B) survival pathway.
In HT-29 colorectal cancer cells, anticancer activity occurs through the suppression of phosphoinositide 3-kinases (PI3K) and Akt, key regulators of cell survival and proliferation.
Meanwhile, in leukemia cell lines A230.
InsPCI causes G2/M phase cell cycle arrest.
Complementing these findings, studies in prostate cancer mouse models demonstrated that InsPCI reduces tumor growth, progression, and aggressiveness through several pro-apoptotic mechanisms.
Beyond InsPCI alone, synergistic and derivative effects have also been observed.
Combination of histone with InsPCI enhances pro-apoptotic activity in oral and nasopharyngeal carcinoma HONE-1 cells.
Combining InsPCI with histone reduced the concentration required to induce apoptosis in HeLa cells by almost 10-fold compared to InsPCI alone.
Moreover, structurally related compounds such as InsPCI and InsPCE have shown anticancer activity.
InsPCI suppresses angiogenesis and tumor progression by inhibiting hypoxiainducible factor (HIF)-1 and vascular endothelial growth factor (VEGF).
In addition.
InsPCE exerts anticancer potential by interfering with molecular mechanisms that promote metastasis and tumor cell proliferation.
The anticancer effects of InsPCI are primarily mediated through the regulation of apoptotic pathway.
Regulation of extrinsic and intrinsic apoptotic pathways has been reported as a key mechanism through which InsPCI contributes to its anticancer activity.
The extrinsic pathway is initiated by extracellular signals that bind to death receptors, leading to activation of caspase-8 through death-inducing signaling.
contrast, the intrinsic pathway is triggered by intracellular stress such as DNA damage or oxidative imbalance.
Caspase-2 contributes to apoptosis by responding to DNA damage, functioning as a tumor suppressor, and maintaining genomic stability as well as cell cycle regulation.
Both pathways lead to the activation of executioner caspases, particularly caspase-3, which facilitates mitochondrial cytochrome c release and drives the execution phase of .
Although the anticancer activity of InsPCI has been reported through caspase activation, there is still no molecular docking evidence that directly examines InsPCI interactions with upstream apoptotic regulators such as caspase-8 in the extrinsic pathway, caspase-2 as a sensor of DNA damage in the intrinsic pathway, and caspase-3 in InsPCI Induces Apoptosis via Caspase-Dependent Pathways (Sandra F, et al.
Indones Biomed J.
: 475-83
the execution phase.
Therefore, this study aimed to perform molecular docking analysis of InsPCI with histones and key caspase proteins to clarify its potential binding mechanisms.
This approach is expected to enhance the understanding of InsPCI effectiveness and provide new insights into its proapoptotic and anticancer properties.
Methods Ligand and Protein Data Mining All ligand data including Canonical Simplified Molecular Input Line Entry System (SMILES) of Inositol Hexakisphosphate (InsPCI) (Pubchem CID: .
CID:
Inositol-.
,3,4,5,.
-Pentakisphosphate (InsP.
(Pubchem CID: 17754.
Inositol-.
,4,5,.
-Tetrakisphosphate (InsP.
(Pubchem CID: 443.
, histone deacetylase inhibitor (Pubchem CID: 5353.
Z-IETD-FMK caspase-8 inhibitor (Pubchem CID: 25108.
Z-VDVADFMK caspase-2 inhibitor (Pubchem CID: 25108.
, and Ac-DEVD CMK caspase-3 inhibitor (Pubchem CID:
were obtained and downloaded in sdf format.
Ligands were selected based on structural relevance to the target compounds for subsequent analysis.
Target protein data of histone (PDB ID: 8JCC), caspase-8 (PDB ID: 5L.
, caspase-2 (PDB ID: 1PYO), caspase-3 (PDB ID: 3KJF) were retrieved and downloaded in PDB format.
Proteins were selected based on good resolution .
0Ae2.
5 yI), absence of mutations, 90% residues in favored regions, and 0% in disallowed regions.
InsPCI Toxicity Prediction and Physicochemical Analysis InsPCI toxicity prediction was conducted using ProTox-3.
(Environmental Protection Agency.
Washington DC.
USA) at .
ttps://tox.
de/protox3/).
Canonical SMILES was input to detect toxicity class, hepatotoxicity, immunotoxicity, mutagenicity, and cytotoxicity.
InsPCI analysis was conducted using SwissADME (Molecular Modeling Group.
Lausanne.
Switzerlan.
ttp://w.
Canonical SMILES was input to analyze molecular weight, molar refractivity, lipophilicity, water solubility, number of heavy atoms, rotatable bonds, hydrogen bond acceptors, and hydrogen bond donors.
Ligand and Protein Preparation Each ligand was prepared by performing energy minimization with PyRx-Virtual Screening Tool (FastSpring.
Amsterdam.
Netherland.
Briefly, each ligand The Indonesian Biomedical Journal.
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October 2025, p.
structure was imported into the workspace and subjected to energy minimization using the Universal Force Field (UFF).
Ligand optimization was performed using the conjugate gradient method with a maximum of 200 steps.
Convergence was considered achieved when the energy gradient was 01 kcal/molAyI, ensuring that the ligands adopted the most stable 3D conformation.
Minimized ligand structures were then exported and saved in PDB format for further analysis.
Meanwhile, each protein was prepared by removing water molecules and bound ligands using Biovia Discovery Studio 2016 (Dassault Systymes.
Vylizy-Villacoublay.
Franc.
Briefly, crystal structures of the proteins were obtained from PDB loaded into the software.
Water molecules, co-crystallized ligands, and other non-essential heteroatoms were removed to prevent interference during the docking process.
The cleaned and optimized protein structures was then saved and further converted into PDB Molecular Docking Analysis Molecular docking analysis was performed using CB-Dock .
ttps://cadd.
cn/cb-dock2/php/index.
Prepared ligand and protein were input to detect ligandprotein interactions and possible bindings.
Molecular docking was performed using CB-Dock2.
0, which automatically detects up to five potential binding cavities and applies AutoDock Vina as the docking engine.
For each cavity, multiple binding poses were generated, and the best pose was selected based on the lowest Vina score binding affinity .
cal/mo.
and cavity suitability.
Visualization of three-dimensional .
D) and two-dimensional .
D) interactions were carried out using Biovia Discovery Studio Results Toxicological Profiles and Physiochemical Properties of InsPCI Toxicity prediction using the ProTox-i platform classified InsPCI into toxicity Class IV, suggesting relatively low acute Furthermore.
InsPCI was predicted to be inactive across all evaluated toxicity endpoints (Table .
Based on its physicochemical properties.
InsPCI was identified as a highly polar and water-soluble compound.
The compound exhibited a high number of hydrogen bond donors and acceptors, which contributed to its strong hydrophilicity.
This was further supported by its negative log P value.
Print ISSN: 2085-3297.
Online ISSN: 2355-9179 Table 1.
Toxicity prediction profiles of InsPCI using Pro-Tox i.
Toxicity Test Toxicity Class (LD.
Ligand InsP6 Class 4 .
0 mg/k.
Hepatotoxicity Inactive .
Immunotoxicity Inactive .
Mutagenicity Inactive .
Cytotoxicity Inactive .
LDCICA: lethal dose for 50% of the test population.
Substances in Class I (LDCICA O 5 mg/k.
and Class II .
mg/kg < LDCICA O 50 mg/k.
are considered fatal if ingested.
Class i compounds .
mg/ kg < LDCICA O 300 mg/k.
are categorized as toxic, whereas Class IV .
mg/kg < LDCICA O 2000 mg/ k.
is regarded as harmful.
Class V substances .
0 mg/kg < LDCICA O 5000 mg/k.
may still pose harmful effects, while Class VI (LDCICA > 5000 mg/ k.
is classified as non-toxic.
indicating low lipophilicity (Table .
Following toxicity prediction, docking analysis was conducted to examine proteinAeligand interactions.
Molecular Docking Interaction of InsPCI and Histone Molecular docking results showed that InsPCI had a stronger binding Vina score with the histone compared to histone protein-histone deacetylase inhibitor (Table .
InsPCI Table 2.
Physiochemical properties of InsPCI using SwissADME web-based platform.
Physiochemical Ligand InsP6 Molecular Weight .
/mo.
Number of Heavy Atoms Number of Rotatable Bonds Number of HBA Number of HBD Molar Refractivity Lipophilicity (Log P) Water Solubility (Log S / ESOL) HBA: Hydrogen Bond Acceptors.
HBD: Hydrogen Bond Donors.
Log P: logarithm of the partition Log S: Logarithm of the aqueous ESOL: Estimated Solubility.
InsPCI Induces Apoptosis via Caspase-Dependent Pathways (Sandra F, et al.
Indones Biomed J.
: 475-83
DOI: 10.
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Table 3.
Molecular docking interactions of histone protein complex with InsP6 and histone deacetylases inhibitor.
Vina Score cal/mo.
Hydrogen Bond Details Van Der Waals Bond Other Bonds InsP6 ARG17.
GLY11.
GLY9,
GLY2.
LYS5,SER1
ARG3.
GLY4.
LEU10,
LYS16,
N/A
Histone deacetylase inhibitor ARG45.
GLY41
ILE46.
ILE50.
ILE34.
SER47,
THR54.
VAL43,
Ligand Pi-Sigma: ALA38 Amide-Pi Stacked: LEU37 formed multiple hydrogen bonds with key histone residues, including ARG17.
GLY2.
GLY11.
GLY9.
LYS5, and SER1.
In contrast, histone protein and histone deacetylase inhibitor exhibited fewer hydrogen bonds, involving only ARG45 and GLY41 (Figure .
hydrogen bonds with ARG156.
GLU287.
GLN129.
LYS225, and TYR221.
This binding interaction was comparable to Z-VDVAD, which formed hydrogen bonds with ASN232.
ARG231.
THR233, and TYR273 (Figure 3.
Table .
Molecular Docking Interaction of InsPCI and Caspase-8 InsPCI demonstrated a strong binding affinity with caspase-8.
The affinity was comparable to the Z-IETDAecaspase-8, the reference inhibitor (Table .
Molecular docking analysis showed that InsPCI interacted with caspase-8 through hydrogen bonding with ARG47 and LYS121 (Figure .
Molecular Docking Interaction of InsPCI.
InsPCE.
InsPCI, and Caspase-3 InsPCI also exhibited strong binding affinity to caspase-3.
Similarly, the small difference in Vina scores between the InsPCIAecaspase-3 and proteinAeinhibitor binding supported this finding, suggesting that InsPCI bound to caspase-3 with an affinity comparable to that of the reference inhibitor (Table .
In addition.
InsPCI formed hydrogen bonds with several residues of caspase-3, including ARG207.
ARG64.
CYS163.
HIS121, and SER120 (Figure .
Molecular Docking Interaction of InsPCI and Caspase-2 Molecular docking analysis showed that InsPCI bound to the active site of caspase-2 with a high binding affinity, forming Figure 1.
3D and 2D interaction between histone protein complex and two ligands: InsP6 and histone deactylase inhibitor.
The red rectangle highlights the binding sites of both ligands within the active site of the histone protein complex .
rown colour with ribbon patter.
A: 3D interaction of InsP6 with the histone protein complex.
B: 2D
interaction of InsP6 with the histone protein complex.
C: 3D interaction of the histone deacetylase inhibitor with the histone protein complex.
D: 2D
interaction of the histone deacetylase inhibitor with the histone protein The Indonesian Biomedical Journal.
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October 2025, p.
Print ISSN: 2085-3297.
Online ISSN: 2355-9179 Table 4.
Molecular docking interactions of caspase-8 with ligand target InsP6 and Z-IETD-FMK.
Ligand
InsP6
Z-IETD-FMK
Vina Score cal/mo.
Hydrogen Bond Details Van Der Waals Bond Other Bonds ARG47.
LYS121
CYS131.
GLN125.
GLU110.
GLN46,
LEU124.
LEU133.
MET43.
PHE122,
SER113
Attractive Charge: ASP135.
GLU50.
GLU111.
GLU116
ASN168.
GLU111.
GLN125,
GLN49.
SER170,
ARG47.
ASP2.
GLU50.
GLU55,
GLU56.
GLU126.
GLN46.
GLN107,
GLU116.
LEU54.
LEU42.
PHE45,
SER129.
SER4.
SER113
All binding of InsPCI.
InsPCI, and InsPCE with caspase-3 showed a similar binding ability.
Vina scores showed only slight differences among the three ligands (Table .
InsPCI.
InsPCI, and InsPCE had some similar hydrogen and Van Der Waals bond residues (ARG207.
ALA162.
GLY122.
CYS163.
HIS121, and TRP.
(Figure .
Discussion InsPCI has been reported to require relatively high concentration for inducing apoptosis in cancer cells.
In addition, in the present study for toxicity prediction.
InsPCI was classified to have a low acute toxicity at specific dosage levels (Table .
, suggesting a relatively safe toxicity profile Alkyl/Pi-Alkyl: ILE174.
LEU7 Halogen (Fluorin.
CYS131.
GLU110
for InsPCI.
From the physicochemical profile.
InsPCI has been shown to have high polarity and hydrogen bonding capacity (Table .
, which might cause limited membrane permeability, leading to reduction of absorption and transport across biological membranes.
Therefore, formulation strategies had been pursued to improve permeability of InsPCI.
One reported approach involved binding InsPCI to .
In the present study, molecular docking analysis indicates that InsPCI exhibited stable binding to the histone, comparable to the binding observed with the control (Table .
Previous studies indicate that histone binding can facilitate the cellular uptake of InsPCI.
Moreover, the binding of histone was shown to increase potential of InsPCI in inducing apoptosis, so that a high concentration of InsPCI was no longer required.
Collectively, these findings Figure 2.
3D and 2D interaction between caspase-8 protein complex and two ligands: InsP6 and Z-IETDFMK.
The red rectangle highlights the binding sites of both ligands within the active site of the caspase-8 protein complex .
agenta colour with ribbon A: 3D interaction of InsP6 with the caspase-8 protein complex.
B: 2D interaction of InsP6 with the caspase-8 protein complex.
C: 3D
interaction of the Z-IETD-FMK with the caspase-8 protein complex.
D: 2D
interaction of the Z-IETD-FMK with the caspase-8 protein complex.
InsPCI Induces Apoptosis via Caspase-Dependent Pathways (Sandra F, et al.
Indones Biomed J.
: 475-83
DOI: 10.
18585/inabj.
suggest that histone play an important role in enhancing pro-apoptotic efficacy of InsPCI.
InsPCI has been demonstrated to induce anticancer effects through the extrinsic apoptotic pathway, with caspase-8 playing a central role.
,6,.
Molecular docking results indicated that InsPCI bound strongly to the active site of the caspase-8 protein (Table .
These results suggest that InsPCI may support the potential of InsPCI as an anticancer Figure 3.
3D and 2D interaction complex and two ligands: InsP6 and Z-VDVAD.
The red rectangle highlights the binding sites of both ligands within the active site of the caspase-2 complex .
urple colour with ribbon patter.
A: 3D interaction of InsP6 with the caspase-2 protein B: 2D interaction of InsP6 with the caspase-2 protein complex.
3D interaction of the Z-VDVAD with the caspase-2 protein complex.
D: 2D
interaction of the Z-VDVAD with the caspase-2 protein complex.
Table 5.
Molecular docking interactions of caspase-2 with InsP6, and Z-VDVAD.
Ligand
InsP6
Z-VDVAD
Vina Score cal/mo.
Hydrogen Bond Details Van Der Waals Bond Other Bonds ARG156.
GLN129.
GLU287.
LYS225.
TYR221
CYS289.
CYS219.
GLY116,
LEU224.
PHE132
Attractive Charge:
GLU287.
GLU115
ALA229.
ARG54.
ASP158,
GLU52.
HIS112.
MET230,
PHE53.
TRP238.
THR277,
Alkyl/Pi-Alkyl: ALA274.
ALA228.
LYS234
ASN232.
ARG231,THR233,
TYR273
Pi-Pi T-shaped: PHE279 Pi-Sulfur: CYS155 Table 6.
Molecular docking interactions of caspase-3 with InsP6.
InsP5.
InsP4, and Ac-DEVD-CMK.
Vina Score cal/mo.
Hydrogen Bond Details Van Der Waals Bond InsP6 ARG207.
ARG64.
CYS163,
HIS121.
SER120
ALA162.
GLY122.
SER63.
SER205.
THR62.
TRP206,
TYR204
InsP5 ARG207.
CYS163.
HIS121,
SER205.
TYR204,
ALA162.
GLN161.
GLY122.
MET61.
PHE256.
SER120,
SER63.
TRP206.
THR166.
THR62,
InsP4 ARG207.
ARG64.
CYS163,
HIS121.
SER205.
SER120.
THR62
ALA162.
GLY122.
GLN161.
MET61.
SER209,
TRP206.
TYR204
Ac-DEVD-CMK ARG207.
ARG64.
ASN208,
THR62.
TRP214
CYS163.
HIS121.
HIS257.
LYS210.
PHE250.
PHE256,
SER205.
SER249.
SER251.
TRP206.
TYR204
Ligand The Indonesian Biomedical Journal.
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Print ISSN: 2085-3297.
Online ISSN: 2355-9179 Figure 4.
3D and 2D interaction between caspase-3 protein complex and three ligands: InsP6.
InsP5.
InsP4, and Ac-DEVD-CMK.
The red rectangle highlights the binding sites of ligands within the active site of the caspase-3 protein complex .
ellow colour with ribbon patter.
A: 3D
interaction of InsP6 with the caspase-3 protein complex.
B: 2D interaction of InsP6 with the caspase-3 protein C: 3D interaction of InsP5 with the caspase-3 protein complex.
D: 2D
interaction of InsP5 with the caspase-3 protein complex.
E: 3D interaction of InsP4 with the caspase-3 protein F: 2D interaction of InsP4 with the caspase-3 protein complex.
3D interaction of Ac-DEVD-CMK with the caspase-3 protein complex.
H: 2D
interaction of Ac-DEVD-CMK with the caspase-3 protein complex.
agent by targeting key component of the extrinsic apoptosis This outcome reflects previous findings that confirm InsPCI can induce apoptotic cell death in HT-29 colorectal cancer cells by increasing the expression and activity of caspase-8.
Several apoptotic processes are influenced by alterations in mitochondrial membrane potential mediated by caspase-2, which has been reported to be activated by its specific trigger.
In this study.
InsPCI exhibits strong binding to active site of caspase-2 through hydrogen.
Van der DOI: 10.
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Waals, and attractive charge interactions (Figure 3.
Table .
These results suggest that InsPCI has the potential to modulate caspase-2 activity within the intrinsic apoptotic pathway.
In this pathway, caspase-2 could initiate apoptosis by cleaving BH3 Interacting Domain (BID) into truncated BID .
BID), which in turn promotes mitochondrial outer membrane permeabilization (MOMP).
This event triggers the release of cytochrome c, leading to the formation of the apoptosome and subsequent activation of downstream effector caspases, including caspase-3.
The initiator caspase-8 and caspase-2 play a pivotal role in triggering apoptosis.
However, the apoptotic cascade can be attenuated by inhibitory molecules, particularly those belonging to the inhibitor apoptosis protein (IAP).
In the present study.
InsPCI exhibited strong docking interactions not only with initiator caspases but also with the effector caspase-3 (Figure 4.
Table .
Previous reports have also highlighted anticancer potential of other inositol phosphates, such as InsPCI and InsPCE.
Molecular docking analysis showed that InsPCI binds to caspase-3 at several active sites similar to InsPCI and InsPCE, suggesting that InsPCI may contribute to apoptosis induction (Figure 4.
Table .
InsPCI has been demonstrated to induce apoptosis, supported by molecular docking interactions with apoptotic The apoptosis can be induced through diverse mechanisms including caspase-dependent/independent The present results indicate that InsPCI engages caspase-mediated mechanisms, highlighting its potential role in regulating apoptosis.
Nevertheless.
InsPCI may also act through caspase-independent pathways.
Therefore, the caspase-independent pathway should be explored further to have a better understanding of InsPCI anticancer role in inducing apoptosis.
In addition, since this study only utilized computer-based analysis, which provided results that may be useful.
however, these findings need to be further confirmed and explored through in vitro analysis.
Conclusion InsPCI exhibited low acute toxicity, suggesting a favorable safety profile.
The strong binding between histones and InsPCI as confirmed by molecular docking results, could increase the potency of InsPCI in inducing apoptosis.
The apoptosis induced could be triggered through both caspasedependent extrinsic and intrinsic apoptosis pathways.
Taken together.
InsPCI may act as a potential inducer of apoptosis in cancer cells.
InsPCI Induces Apoptosis via Caspase-Dependent Pathways (Sandra F, et al.
Indones Biomed J.
: 475-83
Authors Contribution FS concepting and planning the research.
DR.
JH.
AP, and KHL contributed additional ideas.
FS and VEP performed FS concepting and planning the research.
DR.
JH.
AP, and KHL contributed additional ideas.
FS and VEP performed the data acquisition/collection, performed the data analysis, drafted the manuscript, designed the figures.
All authors took parts in giving critical revision of the manuscript.
Conflict of Interest The authors declare no conflicts of interest or competing interests related to the content of this manuscript.
References