Synergies

Synergy occurs when two or more substances work together to create an effect greater than the sum of their individual effects. For instance, to achieve the best possible results when cleaning dishes in a dishwasher, it's not enough to have a high-quality detergent—you also need dishwasher salt and rinse aid. Using all three products together you get the best result.

Combining natural substances, repurposed drugs, and conventional treatments like chemotherapy and immunotherapy for cancer can provide a multi-pronged approach that targets different aspects of cancer biology. Synergistic combinations may improve therapeutic outcomes by enhancing efficacy, reducing side effects, and overcoming resistance to conventional treatments.

Here are some examples of synergistic strategies:

Natural Substances with Chemotherapy and Immunotherapy

Curcumin (from turmeric) + chemotherapy: Curcumin exhibits anti-inflammatory, antioxidant, and anticancer properties. It can sensitize cancer cells to chemotherapy agents like cisplatin, paclitaxel, and doxorubicin by enhancing apoptosis, inhibiting NF-κB, and reducing multidrug resistance (MDR) proteins.

Panax Ginseng + immunotherapy: Ginsenosides modulate immune responses, promoting the activity of CTLs and NK cells. They also reduce Treg activity and can enhance the efficacy of immune checkpoint inhibitors.

Repurposed Drugs in Combination with Conventional Treatments

Metformin (an antidiabetic drug) + chemotherapy: Metformin can inhibit the mTOR pathway involved in cancer cell growth and metabolism. Its combination with chemotherapy (e.g., doxorubicin) can reduce tumor growth and enhance chemotherapy sensitivity, especially in breast and colorectal cancers.

Chlorpheniramine (antihistamine) + chemotherapy: Chlorpheniramine shows antiproliferative and cytotoxic effects on cancer cells. Combined with standard chemotherapeutics, it may help enhance cancer cell death by modulating oxidative stress and calcium influx, making the cancer cells more vulnerable to chemotherapy-induced damage.

Natural Substances with Repurposed Drugs

Shikonin (from Lithospermum erythrorhizon) + metformin: Shikonin, which inhibits glycolysis and fatty acid synthesis while activating AMPK, can synergize with metformin’s effects on metabolic pathways, resulting in enhanced tumor suppression, particularly in cancers reliant on altered metabolic states like hepatocellular carcinoma (HCC).

Combination of Glycolysis Inhibitors and Immune Modulators

Galla Chinensis (gallic acid) + checkpoint inhibitors: Gallic acid inhibits LDHA and disrupts glycolysis, starving cancer cells of energy. Combined with immune checkpoint inhibitors like anti-PD-1/PD-L1 therapies, this approach can enhance T-cell function and potentially reverse the immunosuppressive tumor microenvironment.

Astragalus polysaccharides (APS) + PD-L1 blockade: APS has been shown to enhance antitumor immune responses by modulating PD-L1 expression and boosting CD8⁺ T cell infiltration. This makes it a candidate for combination with PD-L1/PD-1 inhibitors to improve immunotherapy outcomes, especially in liver and lung cancers.

Fatty Acid Metabolism Modulators with Chemotherapy

Baicalin + paclitaxel or cisplatin: Baicalin promotes fatty acid oxidation (FAO) and may enhance the efficacy of chemotherapy by inducing metabolic stress in cancer cells. When combined with chemotherapeutic agents like paclitaxel, it can lead to increased tumor cell death.

Omega-3 fatty acids (e.g., DHA) + chemotherapy: DHA can enhance the sensitivity of cancer cells to chemotherapy by modulating cell membrane fluidity, reducing inflammation, and inducing apoptosis through oxidative stress mechanisms. In combination with cisplatin or doxorubicin, omega-3s can increase the therapeutic index of these drugs.

Combination of Immune Modulation and Metabolic Disruption

Rosmarinic acid (RA) + ginsenoside Rg1 + COX-2 inhibitors: Both RA and Rg1 show antimetastatic effects in colorectal cancer (CRC) by modulating immune checkpoints (e.g., PD-1/PD-L1) and COX-2, which are involved in inflammation-driven tumor progression. Combining these natural compounds with COX-2 inhibitors could suppress metastasis and enhance the efficacy of immunotherapy.

Natural Substances as Radiosensitizers

Green tea polyphenols (EGCG) + radiotherapy: Epigallocatechin gallate (EGCG), the main polyphenol in green tea, can act as a radiosensitizer by promoting DNA damage in cancer cells while protecting normal cells from radiation-induced harm. This dual effect makes EGCG a candidate for enhancing the therapeutic ratio of radiotherapy.

Silymarin + radiotherapy: Silymarin, a flavonoid complex from milk thistle, has antioxidant and cytotoxic properties that may enhance the effects of radiotherapy on cancer cells while protecting normal cells from oxidative damage, thereby improving the selectivity of radiation treatment.

Combination of Natural Products 

Natural compounds that can inhibit cancer growth and proliferation through multiple mechanisms.

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Considerations

When developing synergistic combinations, it’s important to account for the unique characteristics of the tumor type, its metabolic dependencies, the specific molecular pathways involved, and the safety of these combinations, especially when using untested natural substances or off-label repurposed drugs.

These strategies aim to disrupt cancer cells on multiple fronts, metabolically, immunologically, and via conventional cytotoxic means, offering a comprehensive and potentially more effective treatment approach.

Please refer to the spreadsheet for detailed information on the effects of over 100 supplements, repurposed drugs, and conventional treatments across more than 30 anticancer variables.