SYNERGETIC THERAPEUTIC EFFECT OF TQ + CHRYSIN AS AN ANTICANCER AGENT
Field and Rationale
This invention relates to oncology nutrition compositions comprising thymoquinone (TQ) and chrysin (5,7dihydroxyflavone) for use as adjunctive nutritional therapy in patients with solid and hematological malignancies. The combination targets key cancer hallmarks—uncontrolled proliferation, resistance to apoptosis, angiogenesis, metabolic reprogramming, oxidative stress, inflammation, and epigenetic dysregulation—through complementary mechanisms.
The composition is intended as a specialized medical food or nutraceutical to be administered alongside standard chemo, radio, endocrine or immunotherapies to improve tumor control, support host immunity, and reduce treatmentrelated toxicity without exhibiting direct chemotoxicity at nutritional doses.
Chemical Identity and Structures
Thymoquinone
- IUPAC name: 2methyl5isopropyl1,4benzoquinone.
- Molecular formula: C10_ {10}10H12_{12}12O2_22.
- Source: Major bioactive constituent of Nigel sativa (black seed) seed oil.
Structure
Thymoquinone is a 1,4benzoquinone ring bearing a methyl group at position 2 and an isopropyl group at position 5. The ring contains two opposite carbonyl (C=O) groups (quinone), making TQ a redoxactive molecule capable of cycling between quinone and hydroquinone forms and generating reactive oxygen species (ROS) in a controlled manner.
Chrysin
- IUPAC name: 5,7dihydroxy2phenyl4Hchromen4one.
- Molecular formula: C15_{15}15H10_{10}10O4_44.
- Source: Natural flavonoid present in honey, propolis and passion flower species
Structure
Chrysin is a flavone with a threering system (A, B, C): a benzopyranone (chromen4one) core with a phenyl ring at position 2. It has hydroxyl (–OH) groups at positions 5 and 7 on the Aring, which confer antioxidant, metalchelating, and signalingmodulatory properties.
Inhibition of Proliferation and Cell Cycle
- TQ inhibits proliferation of multiple cancer cell lines (e.g., prostate, osteosarcoma, hepatocellular carcinoma, colon, breast) and can induce G2/M cell cycle arrest.
- It downregulates prosurvival pathways such as PI3K/AKT and ERK, leading to reduced phosphorylation of downstream targets that drive growth and survival.
Induction of Apoptosis
- TQ activates both intrinsic (mitochondrial) and extrinsic (death receptormediated) apoptosis pathways
- It increases expression of proapoptotic mediators (TRAIL, death receptor 5, caspases9, 8, 3, BclxS_SS) and reduces antiapoptotic Bcl2.
- This restores apoptotic balance in cancer cells, promoting selective death of malignant cells while sparing normal cells at appropriate doses.
Antiangiogenic and Antimetastatic Effects
- TQ inhibits endothelial cell migration, invasion, proliferation and tube formation in vitro, and suppresses tumor angiogenesis and tumor growth in vivo.
- Mechanistically, TQ interferes with VEGFinduced ERK and AKT activation in endothelial cells and suppresses NFκB and its regulated proangiogenic genes
- In mouse xenograft models, lowdose TQ inhibits tumor growth and vascularization with minimal chemotoxicity.
Modulation of Oxidative Stress and Inflammation
- TQ acts as a redoxactive molecule that can generate ROS in cancer cells, promoting DNA damage and apoptosis, while enhancing antioxidant defenses in normal tissues.
- It reduces NFκB activation and downstream inflammatory mediators, which are key drivers of cancer progression and cachexia.
Use in Combination Therapies
- TQ has shown synergy with multiple chemotherapeutics and natural compounds, improving cytotoxicity toward cancer cells and overcoming drug resistance with reduced toxicity to normal cells.pmc.ncbi.nlm.nih+1
- TQbased hybrids (e.g., artemisininTQ, artesunic acidTQ) exhibit enhanced antiproliferative activity and ROSmediated apoptosis in cancer cells while sparing normal cells.
Known AntiCancer Actions of Chrysin
Inhibition of Proliferation and Cell Cycle
- Chrysin suppresses cellular proliferation in various cancer models by modulating key signaling pathways (e.g., PI3K/AKT, MAPK) and transcription factors.
- It can induce cell cycle arrest (often via activation of p38 MAPK and modulation of cyclins and CDKs) leading to growth inhibition.
Induction of Apoptosis
- Chrysin induces apoptosis by activating caspase3 and caspase9 and increasing Bax expression, indicating engagement of the intrinsic mitochondrial pathway.pmc.ncbi.nlm.nih+1
- In colon cancer models, oral chrysin significantly reduces tumor volume in mice and modulates expression of Bax (up) and the stemnessassociated factor Sall4 (down)
Antiangiogenic and Antiinflammatory Effects
- Chrysin can inhibit tumor cellinduced angiogenesis, contributing to reduced tumor vascularization
- It exerts antiinflammatory effects by suppressing NFκB and related cytokines, thereby interfering with tumorpromoting inflammation.
Metabolic and Epigenetic Modulation
- In hepatocellular carcinoma, chrysin downregulates hexokinase2, decreases glucose uptake and lactate production, and triggers apoptosis, targeting the Warburg effect.
- Chrysin activates TET1 and modulates DNA demethylation in gastric cancer models, leading to growth inhibition via epigenetic reprogramming.
- It also suppresses tumorigenesis by inhibiting histone deacetylase 8 (HDAC8), further influencing cancerrelated epigenetic marks.
Potential Against Chemoresistance
- Due to its multitargeted antitumor activity (cell cycle, apoptosis, metabolism, epigenetics), chrysin may help overcome chemotherapy resistance and enhance the efficacy of conventional agents.
Proposed Synergistic MOA: TQ + Chrysin in Oncology Nutrition
The THYMOQUINONE + CHRYSIN combination is designed to provide multitargeted, nutritionally delivered
modulation of cancer biology and the tumor microenvironment.
modulation of cancer biology and the tumor microenvironment.
Complementary Targeting of Proliferation and Apoptosis
- TQ and chrysin each inhibit proliferation and induce apoptosis through overlapping but nonidentical pathways (AKT/ERK, NFκB, mitochondrial caspases, TRAIL signaling)
- Their combination is expected to:
- Amplify mitochondrial apoptosis via convergent activation of Bax, caspase3 and9, and downregulation of Bcl2 family proteins.
- Enhance extrinsic apoptosis by TQmediated upregulation of TRAIL and death receptor 5, while chrysin improves cellular sensitivity by reducing survival signaling.
Dual Antiangiogenic Action
- TQ potently inhibits endothelial cell functions and VEGFinduced ERK/AKT activation, resulting in reduced tumor angiogenesis in vivo.
- Chrysin additionally blocks tumorinduced angiogenic signaling, thereby reinforcing the antivascular effect of TQ.
- Nutritional codelivery may reduce tumor microvessel density, limiting nutrient supply and metastatic potential.
Redox and Inflammatory Balance
- TQ’s redoxcycling properties selectively increase ROS in cancer cells, driving apoptosis, while enhancing antioxidant responses in normal tissues.
- Chrysin contributes strong antioxidant and antiinflammatory activity via its phenolic structure, reducing NFκB activity and oxidative damage in normal cells.
- The combination is expected to create a therapeutic redox differential: prooxidant in tumors, protective in normal tissues, especially under oxidative stress from chemo or radiotherapy.
Metabolic and Epigenetic Effects
- Chrysin’s downregulation of hexokinase2 and glycolytic flux targets cancer cell metabolic reprogramming.
- TQ, by modulating mitochondrial function and ROS, also impacts cellular energy metabolism.
- Chrysin’s TET1 activation and HDAC8 inhibition may synergize with TQdriven redox changes to reprogram epigenetic marks associated with proliferation, invasion, and stemness.
- In oncology nutrition, these effects may contribute to more differentiated, less aggressive tumor phenotypes over time.
Support of Host Immunity and Microenvironment Modulation
- TQcontaining regimens have been shown to stimulate anticancer immune responses while limiting chemotoxicity.
- Chrysin’s antiinflammatory and antioxidant actions may protect immune cells from therapyinduced damage and chronic inflammatory stress.
- A TQ + chrysin nutritional formulation can help maintain immune competence and a less tumorpromoting microenvironment during cancer therapy.
Specific Application in Oncology Nutrition
Intended Use
-
Adjunctive nutritional support for patients with:
Solid tumors (breast, colon, gastric, prostate, liver, lung). Hematological malignancies where inflammation, oxidative stress, and metabolic dysregulation are prominent. - Use in all treatment phases: pretreatment, concurrent with systemic therapy, and in survivorship for recurrence risk reduction and metabolic control.
Proposed Oral Nutritional Forms
- Oral solutions, emulsions, softgels, powders, or bars where TQ is delivered in an oil phase and chrysin is cosolubilized or micronized with suitable excipients.
- Codelivery with lipids (e.g., mediumchain triglycerides, phospholipids) to enhance bioavailability of both lipophilic compounds.
- Formulation may include supportive nutrients (e.g., omega3 fatty acids, vitamin D, selenium) provided they do not interfere with the core TQ + chrysin MOA.
Safety and Nutritional Positioning
- TQ from Nigella sativa and chrysin from natural sources have long histories of use as dietary components and nutraceuticals, with favorable safety profiles at nutritional doses
- The formulation is not intended to replace chemotherapy or targeted therapy but to nutritionally modulate pathways that contribute to treatment response, toxicity, and quality of life.
Example Mechanistic Claims (PatentStyle Language)
- A nutritional composition comprising thymoquinone and chrysin for use in reducing tumor angiogenesis in a cancer patient by concurrently inhibiting VEGFinduced ERK and AKT signaling in endothelial cells and suppressing tumorinduced angiogenic signaling
- A nutritional composition comprising thymoquinone and chrysin for use in inducing cancer cell apoptosis by: o upregulating TRAIL, TRAILR2, caspases9, 8, 3 and BclxS_SS; and o increasing Bax expression, activating caspase3 and9, and downregulating Bcl2 and Sall4.
- A method of nutritionally managing cancerassociated metabolic reprogramming comprising administering to a subject in need thereof an effective amount of thymoquinone and chrysin to downregulate hexokinase2, reduce glucose uptake and lactate production, and modulate mitochondrial redox status in tumor cells.
- A method of improving tolerance to chemotherapy or radiotherapy comprising administering a nutritional composition containing thymoquinone and chrysin in an amount sufficient to reduce NFκBmediated inflammation and oxidative damage in nonmalignant tissues while maintaining or enhancing proapoptotic signaling in malignant cells.
Simple MOA Summary (for drawings / flowcharts)
You can convert this into a figure for the patent:
Ingestion
Oral TQ + chrysin → absorption via intestine (lipidassisted).
Systemic distribution
Oral TQ + chrysin → absorption via intestine (lipidassisted).
In microenvironment and host tissues
NFκB and inflammatory cytokines; improved antioxidant status; support of immune function.
In tumor cells
TQ: ↑ ROS → mitochondrial damage → caspase cascade; ↓ AKT/ERK; ↑ TRAIL/DR5; ↓ Bcl2.
Chrysin: ↓ HK2 → ↓ glycolysis; ↑ Bax, caspase3/9; ↓ Sall4; epigenetic modulation via TET1 and HDAC8.pmc.ncbi.nlm.nih+2
Combined: stronger apoptosis, reduced proliferation, less angiogenesis.
Laboratory Infrastructure
Advanced Infrastructure Supporting Precision Research
At Zeed Drops Research Laboratories, our laboratory infrastructure is designed to support structured research, controlled testing, and globally compliant formulation development. Our facilities integrate modern equipment, systematic validation processes, and strict quality monitoring to ensure scientific accuracy and reliability.
RESEARCH DONE BY ABINSHA SHAJU (RESEARCH HEAD- ZEED DROPS RESEARCH LABORATORIES UAE ) AND TEAM.