Anticancer Mechanisms

1. Apoptosis Induction (Programmed Cell Death)

1. Increases Bax/Bcl-2 ratio, promoting mitochondrial outer membrane permeabilisation

2. Triggers cytochrome c release from mitochondria into the cytosol

3. Activates caspase cascade (caspase-9, caspase-3) leading to PARP cleavage

4. Induces dose-dependent apoptosis in multiple cancer cell lines (breast, lung, colon, liver, oral, haematologic)

5. Selective for cancer cells with minimal toxicity to normal cells in comparative studies

2. Cell Cycle Arrest

1. Induces S-phase arrest in lung cancer and osteosarcoma cells

2. Causes G2/M phase arrest in hepatocellular carcinoma

3. Downregulates cyclin D1 expression, reducing cell cycle progression

4. Suppresses proliferation markers, including Ki67

5. Disrupts cell cycle regulatory proteins, preventing uncontrolled division

3. PI3K/AKT and MAPK Pathway Inhibition

1. Blocks phosphorylation of AKT, reducing cancer cell survival signalling

2. Inhibits the PI3K/AKT/mTOR pathway, critical for cancer cell growth and metabolism

3. Suppresses MAPK signalling (ERK1/2, p38, JNK pathways) involved in proliferation

4. Downregulates STAT3 activation, reducing oncogenic transcription

5. Inhibits the NF-κB pathway, decreasing inflammation-driven cancer progression

4. Anti-Metastatic Effects

1. Inhibits epithelial-to-mesenchymal transition (EMT) by upregulating E-cadherin and suppressing N-cadherin

2. Reduces expression of EMT transcription factors (Slug, Snail, Twist)

3. Decreases matrix metalloproteinase (MMP) activity, blocking invasion through the extracellular matrix

4. Suppresses cell migration and invasion in transwell and wound healing assays

5. Prevents lymph node metastases in orthotopic oral cancer models

5. ROS-Mediated Cytotoxicity and Oxidative Stress Modulation

1. Context-dependent dual action: antioxidant in normal cells, pro-oxidant in cancer cells under metabolic stress

2. Activates NOX5-ROS pathway, promoting oxidative DNA damage and ER stress in cancer cells

3. Disrupts mitochondrial membrane potential (MMP), generating reactive oxygen species

4. Inhibits glucose-6-phosphate dehydrogenase (G6PD), limiting NADPH production and antioxidant capacity

5. Causes redox imbalance, particularly lethal to cancer cells with pre-existing oxidative stress

6. ER Stress and Autophagy

1. Triggers endoplasmic reticulum stress response activating UPR (unfolded protein response)

2. Upregulates ER stress markers (CHOP, GRP78, ATF4)

3. Induces autophagy through upregulation of autophagy-related genes

4. ER-mitochondria tethering disruption contributes to cell death

5. Autophagy-mediated cell death in acute myeloid leukemia cells

Secondary Mechanisms

1. Anti-angiogenic effects — suppresses VEGF expression and endothelial cell proliferation, reducing tumour blood vessel formation

2. Drug resistance reversal — overcomes doxorubicin resistance in osteosarcoma by suppressing TUG1/Akt signalling

3. Immune checkpoint modulation — regulates miR-382/PD-L1 axis in colorectal cancer

4. DNA damage enhancement — synergistically increases DNA damage when combined with platinum-based chemotherapy

References for Primary Anticancer Mechanisms

Polydatin enhances oxaliplatin-induced cell death by activating NOX5-ROS-mediated DNA damage and ER stress in colon cancer cells
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1532695/full

Polydatin down-regulates the phosphorylation level of CREB and induces apoptosis in human breast cancer cells
https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0176501

Polydatin inhibits the growth of lung cancer cells by inducing apoptosis and cell cycle arrest
https://pmc.ncbi.nlm.nih.gov/articles/PMC3861602/

A new inhibitor of glucose-6-phosphate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo
https://www.nature.com/articles/s41419-018-0635-5

Polydatin, a Glycoside of Resveratrol, Induces Apoptosis and Autophagy in Oral Squamous Cell Carcinoma
https://pmc.ncbi.nlm.nih.gov/articles/PMC8468100/