Pinocembrin as a novel anti-cancer agent: Exploring preclinical evidence along with therapeutic potential

Table 1 Mapping of pinocembrin’s mechanistic actions to experimental cancer models

Experimental model	Mechanism targeted	Key findings	Ref.
Human cancer cell lines (in vitro)	Mitochondrion-mediated apoptosis	PB stabilized mitochondrial membrane potential, downregulated Bcl-2, promoted Bax translocation, and triggered cytochrome C release. This led to the activation of caspase-9 and caspase-3, resulting in apoptotic cell death	Kumar et al[40], 2007
Cancer cell lines (in vitro)	ROS modulation and mitochondrial function	PB reduced intracellular ROS levels and preserved mitochondrial integrity. By limiting oxidative stress, it disrupted the energy balance necessary for tumor cell proliferation	Gong[41], 2021
Cancer cell lines (in vitro)	Anti-inflammatory and antioxidant pathways	PB inhibited nuclear factor-kappa B activation, which lowered cyclooxygenase-2 and inducible nitric oxide synthase expression. Concurrently, it upregulated endogenous antioxidant enzymes, thereby reducing prostaglandin and nitric oxide production, which support tumor progression	Zhou et al[38], 2015
Animal models and cell assays	Integrated safety, apoptosis, and signaling	Across multiple preclinical models, PB showed minimal toxicity and a broad therapeutic window. It combined pro-apoptotic effects (via the mitochondrial pathway) with anti-inflammatory and antioxidant actions, supporting further development	Elbatreek et al[42], 2023

PB: Pinocembrin; ROS: Reactive oxygen species.

Table 2 Preclinical evidence of pinocembrin’s anti-cancer activity by cancer type

Cancer type	Ref.	Model	Study type	Key findings
Breast cancer	Kumar et al[40], 2007	MCF-7, MDA-MB-231, SKBR3 cells; MCF-7 subcutaneous xenograft (mice)	In vitro and in vivo	PB induced G2/M cell-cycle arrest and apoptosis in MCF-7, MDA-MB-231, and SKBR3 cells by downregulating cyclin B1, Cdc2, PARP1, Bcl-2, and survivin, while upregulating cleaved PARP1, cleaved caspase-3/caspase-9, and Bax. In mice, oral PB suppressed MCF-7 tumor growth without overt toxicity, correlating with PI3K/AKT pathway inhibition
Colorectal cancer	León-González et al[66], 2014	HT-29 and HCT-116 cells	In vitro	PB triggered Bax-dependent mitochondrial apoptosis, evidenced by cytochrome C release and caspase-9/caspase-3 activation. It suppressed proliferation and survival signaling in colon cancer cells
Colorectal cancer	Jiang et al[64], 2022	HCT116, HT29 cells; HCT116 xenograft (mice)	In vitro and in vivo	PB inhibited the proliferation, migration, and invasiveness of HCT116 and HT29 cells by downregulating MMP-2 and N-cadherin and upregulating E-cadherin via LACTB modulation. In HCT116 xenografts, oral PB reduced tumor volume and metastasis
Melanoma	Zheng et al[68], 2018	A375 and B16F10 cells; B16F10 syngeneic mouse model (mice)	In vitro and in vivo	PB inhibited proliferation of A375 and B16F10 cells via endoplasmic reticulum stress (IRE1α/Xbp1) and caspase-12/caspase-4-mediated apoptosis and suppressed autophagy through PI3K/AKT/mTOR activation. In B16F10-bearing mice, oral PB (20 mg/kg) reduced tumor growth and induced apoptosis
Ovarian cancer	Gao et al[51], 2019	SKOV3 and OVCAR-3 cells	In vitro	PB inhibited proliferation (IC50 approximately 60 µM), migration, and invasion of SKOV3 and OVCAR-3 cells by downregulating PI3K/AKT signaling (reduced p-AKT, p-mTOR) and MMP-9, while promoting apoptosis (increased cleaved caspase-3 and Bax/Bcl-2 ratio)
Prostate cancer	Shao et al[65], 2021	PC-3 cells	In vitro	PB inhibited PC-3 proliferation and colony formation in a dose-dependent manner, induced G0/G1 cell-cycle arrest, increased reactive oxygen species production, and promoted apoptosis via regulation of caspase-3/caspase-9, Bax, and Bcl-2
Lung cancer	Gong[41], 2021	A549 cells	In vitro	PB suppressed A549 proliferation (25-200 µM) by restraining autophagy (reduced Beclin-1, light chain 3-II), enhanced apoptosis (increased caspase-3 activity), and reduced colony formation. Autophagy activator (rapamycin) reversed these effects, confirming Pino’s anti-proliferative, anti-autophagic, and pro-apoptotic roles
HCC	Saengboonmee et al[54], 2024	HepG2 and Li-7 cells	In vitro	PB caused G1 arrest in HepG2 and Li-7 cells by downregulating cyclin D1, cyclin E, CDK4, and CDK6; higher doses induced apoptosis (increased sub-G1). It suppressed STAT3 phosphorylation (Tyr705/Ser727), leading to decreased expression of downstream anti-apoptotic genes
HCC	Kurma et al[67], 2021	Rat DEN-induced hepatocarcinogenesis model; colon cancer xenograft (rats)	In vivo	PB neither inhibited nor prevented DEN-induced GST-P foci formation in rat liver; high doses (10 mg/kg) slightly increased GST-P foci, indicating no chemopreventive effect and potential promotion of preneoplastic lesions

AKT: Protein kinase B; CDK: Cyclin-dependent kinase; DEN: Diethylnitrosamine; GST-P: Glutathione S-transferase P; HCC: Hepatocellular carcinoma; MMP: Matrix metalloproteinase; mTOR: Mammalian target of rapamycin; PARP: Polyadenosine-diphosphate-ribose polymerase; PB: Pinocembrin; PI3K: Phosphoinositol-3 kinase.

Table 3 Comparative summary of nanocarrier-based pinocembrin formulations

Formulation type	Particle size (nm)	Entrapment efficiency (%)	Fold bioavailability increase	Half-life (t1/2) extension	Ref.
MPEG-PDLLA micelles (PCB-M)	27.6 ± 0.17	90.5	5.3-fold	1.2 hours increased to 2.6 hours	Cao et al[36], 2022
TPGS micelles	Approximately 50	Approximately 85	4.8-fold	Not reported	Sun et al[84], 2016
TPGS liposomes	Approximately 120	> 85	1.96-fold	1.2 hours increased to 14.2 hours	Tan et al[85], 2013

TPGS: D-α-tocopheryl polyethylene glycol 1000 succinate.