Colon cancer

Evidence-Based Guide to Repurposed Drugs and Natural Substances For Colorectal Cancer Treatment

This comprehensive table synthesizes current evidence for repurposed drugs and natural substances in colorectal cancer treatment. Ranked by clinical evidence and mechanistic understanding, these agents offer promising adjunctive approaches to conventional therapy, with several advancing through clinical trials and demonstrating significant efficacy in prevention and treatment protocols.

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Evidence-Based Agents

Treatment Categories Overview

The table encompasses two primary categories of therapeutic agents, each with distinct advantages and clinical development status. Understanding these categories helps guide treatment selection and combination strategies.

Repurposed Drugs

FDA-approved medications with established safety profiles being investigated for anticancer properties.

Natural Products

Plant-derived compounds with demonstrated anticancer activity in preclinical and clinical studies.

Evidence-Based Treatment Table

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	Substance	Type	Key Mechanism(s)	Key Efficacy Data	Typical Dose & Form	Trial Status	Safety Considerations
1	Aspirin	Repurposed Drug	COX-1/2 inhibition, Wnt/β-catenin suppression, NF-κB inhibition	51-58% recurrence reduction in PIK3CA-mutated CRC; 15-20% incidence reduction	75-160 mg/day (oral)	Phase III Completed	GI bleeding risk
2	Vitamin D	Natural Product	VDR activation, Wnt inhibition, cell cycle arrest (p21/p27)	36% reduced progression risk; PFS 13 vs. 11 months (SUNSHINE trial)	4000 IU/day (oral); target serum 100-150 nmol/L	Phase II/III Ongoing	Excellent below 10,000 IU/day; monitor calcium
3	Metformin	Repurposed Drug	AMPK activation, mTOR inhibition, metabolic reprogramming	8-37% incidence reduction (epidemiological); adenoma prevention	250-2000 mg/day (oral)	Phase II/III Ongoing (e.g., ASAMET)	Contraindicated in renal impairment
4	Omega-3 (EPA)	Natural Product	COX-2/PGE2 suppression, membrane modification, TRAIL apoptosis	25% mortality reduction in Stage III CRC; 30-50% ACF reduction	2-3 g/day EPA (free fatty acid form preferred)	Observational & Ongoing Adjuvant Trials	Excellent; high doses may increase bleeding risk
5	Itraconazole	Repurposed Drug	Hedgehog/SMO antagonism, anti-angiogenic, autophagy	44% response in prostate cancer (proxy data); inhibits xenografts	200-600 mg/day (oral); SUBA-formulation improves absorption	Phase II in various cancers	Tolerated; reversible hepatotoxicity
6	Artemisinin	Natural Product	Ferroptosis, ROS generation via endoperoxide, NF-κB inhibition	High potency (IC50 0.14–0.69 μM); up to 90% apoptosis in combos	1-3 mg/kg (oral, with enhancers)	Phase I in solid tumors	Safe at low doses; neurotoxicity >5 mg/kg
7	Niclosamide	Repurposed Drug	Mitochondrial uncoupling, Wnt/mTOR disruption	Stable disease in clinical trial (NIKOLO); metastasis reduction	2 g/day (oral)	Phase II Recruiting	Excellent record; GI effects
8	Curcumin	Natural Product	NF-κB/COX-2/EGFR modulation, EMT reversal, stem cell targeting	40% ACF reduction at 4 g/day; 60.4% polyp reduction with quercetin	Up to 8 g/day (oral); use enhanced formulations (e.g., Theracurmin)	Phase I/II Completed	Well-tolerated up to 8 g/day
9	Shikonin	Natural Product	PKM2/proteasome inhibition, ER stress, ROS-mediated apoptosis	IC50 3.93-8.61 μM in HCT116/HT29; significant tumor inhibition in xenografts	3-6 mg/kg (IP, 3x/week); requires enhanced formulations	Preclinical / Limited Human Data	Narrow therapeutic window; CYP450 interactions
10	Piperlongumine	Natural Product	TrxR1/GSTP1 inhibition, ROS accumulation, mutant p53 restoration	IC50 10-15 μM in CRC lines; 4.9x reversal of 5-FU resistance	5-10 mg/kg/day (oral); bioavailability >50%	Preclinical / No Human Trials	10-12x cancer selectivity; excellent safety profile
11	Silibinin	Natural Product	NF-κB/Wnt inhibition, cancer stem cell (CD44v6) targeting	42-48% tumor reduction in models	Various (oral); enhanced formulations	Preclinical / Early Clinical	Well-tolerated
12	Honokiol	Natural Product	NF-κB/STAT3/EGFR/mTOR inhibition, Ano1/EMT targeting	Improved survival in models (+21 days)	N/A (preclinical dosing)	Preclinical	Low toxicity in models
13	IV Vitamin C	Natural Product	H₂O₂ pro-oxidant, KRAS/BRAF targeting, HIF-1α inhibition	Improved PFS (13 vs. 8 months) with chemo in mCRC subgroup (RAS mutation only)	1.5-2.2 g/kg IV, 3x/week	Phase III Completed	<2% grade 3+ events; contraindicated in G6PD deficiency
14	Resveratrol	Natural Product	SIRT1 activation, p53 apoptosis, AKT/GSK-3β inhibition	5% proliferation reduction; high colon tissue levels (674 nmol/g)	0.5-1 g/day (oral); with piperine	Phase I/II	Well-tolerated
15	Mebendazole	Repurposed Drug	Microtubule disruption, G2/M arrest, glucose metabolism	62-67% tumor volume reduction in models	Up to 100 mg/kg (preclinical)	Preclinical / Anecdotal	Excellent safety profile as anthelmintic
16	Berberine	Natural Product	AMPK activation, β-catenin downregulation, microbiota modulation	Adenoma reduction in Phase III trial (n=895); 40-60% tumor reduction in models	300 mg twice daily (oral)	Phase III Completed for prevention	Mild GI side effects
17	Thymoquinone	Natural Product	PI3K/AKT/mTOR, Wnt/β-catenin, NF-κB, JAK2/STAT3 inhibition	86% reduction in ACF; IC50 36-284 μM in CRC lines	10 mg/kg/day (Phase I data); requires nanoformulations	Phase I Completed	Excellent safety profile; NOAEL 10 mg/kg
18	EGCG	Natural Product	Hedgehog/PI3K inhibition, immunogenic cell death, GRP78 downregulation	8-fold increase in 5-FU sensitivity in models	1-5 g/day (oral, as green tea extract)	Early Clinical	Hepatotoxicity at very high doses
19	Luteolin	Natural Product	NF-κB/PI3K/MAPK/Notch-1 suppression, EMT inhibition	Metastasis reduction in models	Experimental (preclinical)	Preclinical	Low toxicity in models
20	Sulforaphane	Natural Product	Nrf2 activation, HDAC inhibition, epigenetic modulation	30-60% ACF & polyp reduction in models	30-60 mg/day (from broccoli sprout extract)	Early Clinical / Epidemiological	Well-tolerated
21	Ivermectin	Repurposed Drug	Mitochondrial dysfunction, WNT-TCF/PAK1 inhibition, ROS	>50% tumor growth inhibition in models	Preclinical models	Preclinical / Anecdotal	Well-tolerated at anti-parasitic doses
22	Quercetin	Natural Product	NF-κB/PI3K inhibition, EMT/DKK modulation, radiosensitization	Radiation enhancement in models	>75 mg/day (oral); nano-formulations in development	Preclinical / Early Clinical	Well-tolerated
23	Caffeine/Coffee	Natural Product	Kynurenine pathway suppression, enhanced T-cell antitumor activity	29% reduced mortality (≥4 cups/day post-diagnosis); enhanced immune response	2-4 cups coffee/day (240-480 mg caffeine)	Large Cohort Studies	Well-tolerated; monitor in cardiac conditions
24	Statins	Repurposed Drug	HMG-CoA/mevalonate pathway disruption, YAP/TAZ inhibition	Mixed epidemiological data; up to 47% risk reduction with aspirin	Various standard doses (oral)	Epidemiological / Ongoing Trials	Generally well-tolerated; myopathy risk
25	Losartan	Repurposed Drug	AT1R blockade, PI3K/AKT/mTOR inhibition, anti-angiogenic (VEGF/CD31 reduction), MMP-2/9 suppression	Significant tumor growth reduction in xenografts; enhanced tumor necrosis; synergistic with 5-FU chemotherapy	90 mg/kg/day (preclinical); standard 25-100 mg/day for hypertension	Preclinical / Epidemiological	Excellent safety profile as antihypertensive; monitor renal function
Additional Promising Substances
—	Fucoidan	Natural Product	Apoptosis induction, anti-angiogenic	Tumor growth & survival reduction in models (e.g., with resveratrol)	Oral (preclinical doses)	Preclinical / Limited Human	Generally safe
—	Oleuropein	Natural Product	Proliferation suppression, DNA damage inhibition	84% tumor inhibition in models	N/A (preclinical)	Preclinical	Well-tolerated in models
—	Phenylbutyrate	Repurpused drug	Induced apoptosis in HT-29 colon cancer cells through NF-κB inactivation	Reduces the Proliferation in Colon Cancer Cell Lines Through Modulating the Cell Cycle Regulatory Genes	N/A (preclinical)	Preclinical	Well-tolerated in models

The Wnt/β-catenin signaling pathway is a critical driver of colorectal cancer (CRC), with mutations in APC or related components leading to nuclear β-catenin accumulation and poor prognosis in approximately 90% of cases. Natural compounds often downregulate β-catenin expression or disrupt its nuclear translocation, offering multi-targeted effects with potentially lower toxicity. Examples: Curcumin, EGCG, Luteolin, Apigenin, Myricetin, Magnolol, Piperine, Silibinin, Artemisinin, Vitamin D, Oroxylin-A. Repurposed Drugs as Wnt/β-Catenin Inhibitors: Niclosamide (Highly effective), Celecoxib, Ivermectin, Aspirin, Metformin, Itraconazole.

Synergistic Combinations

Combination therapy approaches can enhance therapeutic efficacy by targeting multiple pathways simultaneously. The following combinations have demonstrated synergistic effects in preclinical studies, offering promising strategies for comprehensive colorectal cancer treatment protocols.

Niclosamide + Metformin

Mechanism: Niclosamide inhibits Wnt/β-catenin signaling to suppress colorectal cancer stem cell proliferation, while metformin activates AMPK and inhibits mTOR pathways.

Efficacy: Over 40% enhanced synergistic inhibition in vitro, significantly reducing CD44+/CD166+ stem-like cell populations and tumor spheroid formation.

Artemisinin + Shikonin: Both induce apoptosis via ROS accumulation; artemisinin's free radical generation may synergize with shikonin's caspase activation.

Curcumin + Berberine: Both activate AMPK and inhibit Wnt/β-catenin; co-treatment reduces recurrent colonic polyps in animal models.

Quercetin + Rutin: Antioxidant and anti-inflammatory effects may compound to enhance colorectal cancer cell inhibition.

⚠️ Combination Therapy Considerations

Synergistic combinations require careful dosing protocols and monitoring for enhanced effects and potential interactions. Professional medical supervision is essential when considering combination approaches.

Key Points:

• Start with lower individual doses when combining agents
• Monitor for additive side effects and drug interactions
• Consider timing and sequencing of administration
• Most combinations require further clinical validation

Important Safety Information

⚠️ Critical Disclaimer

This table is for informational purposes only and does not constitute medical advice. The efficacy and safety of these substances, especially as cancer treatments, are under investigation. Always consult with a qualified healthcare professional before considering any new treatment or supplement, particularly in conjunction with a cancer diagnosis.

Key Considerations:

• Drug interactions may occur with conventional treatments
• Dosing protocols require medical supervision
• Individual patient factors affect suitability and safety
• Quality and standardization vary among suppliers

Abbreviations: ACF: Aberrant Crypt Foci; EMT: Epithelial-Mesenchymal Transition; PFS: Progression-Free Survival; mCRC: metastatic Colorectal Cancer; GI: Gastrointestinal; VDR: Vitamin D Receptor; AMPK: AMP-activated Protein Kinase; COX: Cyclooxygenase; EPA: Eicosapentaenoic Acid

This table integrates data from multiple clinical trials, meta-analyses, and preclinical studies. Evidence quality varies by substance and indication. Last updated: September 2025