Enhancing the Anti-Cancer Effects of High-Ozonide Oil

Targeting Cancer’s Oxidative Vulnerability

Cancer cells exhibit a complex relationship with reactive oxygen species (ROS). While they typically maintain higher baseline oxidative stress levels than normal cells due to rapid proliferation, altered metabolism, and genetic instability, this elevated ROS state paradoxically contributes to oncogenic signaling and enhanced survival mechanisms. However, this adaptation also creates a unique vulnerability, as cancer cells rely heavily on robust antioxidant defense systems to maintain redox balance and avoid cell death.

This precarious redox equilibrium in cancer cells presents a therapeutic window that can be exploited. By strategically elevating ROS levels beyond the cancer cells’ adaptive capacity while simultaneously compromising their antioxidant defenses, it becomes possible to selectively trigger oxidative catastrophe in malignant cells. This approach leverages the cancer cells’ already heightened oxidative state, pushing them towards cell death pathways while largely sparing normal cells due to their lower baseline ROS and more resilient antioxidant systems.

Various therapeutic strategies can be employed to achieve this selective oxidative stress, including:

• ROS-generating compounds
• Inhibitors of key antioxidant pathways
• Multi-pathway disruptors of cancer cell survival mechanisms

By fine-tuning these approaches, we can potentially develop more targeted and effective cancer treatments that exploit the fundamental differences in redox biology between malignant and healthy cells.

Core Treatment

High-ozonide oil (HOO) represents a groundbreaking approach in cancer therapy, harnessing the power of targeted oxidative stress to combat malignant cells. This novel compound delivers a potent payload of ozonides directly to cancer cells and cancer stem cells, triggering a catastrophic elevation of intracellular reactive oxygen species (ROS). Specifically, HOO oxidizes cardiolipin, a key phospholipid in the outer mitochondrial membrane, leading to mitochondrial damage, intracellular calcium release, and apoptosis of cancer cells. This selective effect on cancer cell mitochondria is proposed as the primary mechanism for HOO’s anticancer activity, destroying malignant cells while sparing healthy tissue.

In a landmark clinical trial conducted by Professor Alberto Izzotti, MD. PhD and his team, compelling evidence of HOO’s potential to revolutionize cancer treatment was demonstrated:

• An astounding 80% of patients experienced significant clinical benefits, with 44% achieving full recovery and 36% seeing their cancer downstaged.
• Even in notoriously aggressive and treatment-resistant cancers like glioblastoma and pancreatic adenocarcinoma, HOO demonstrated remarkable efficacy.
• Only 10% of patients had stable disease, while a mere 5% experienced progression or passed away.

These outcomes are far superior to those typically observed with standard treatments alone, and they suggest HOO could be a game-changer in oncology, offering new hope for patients facing limited treatment options. By synergizing with conventional therapies and targeting the fundamental metabolic vulnerabilities of cancer cells, HOO represents a promising new frontier in the fight against this devastating disease.

Reference: Izzotti A, Fracchia E, Rosano C, Comite A, Belgioia L, Sciacca S, Khalid Z, Congiu M, Colarossi C, Blanco G, Santoro A, Chiara M, Pulliero A. Efficacy of High-Ozonide Oil in Prevention of Cancer Relapses Mechanisms and Clinical Evidence. Cancers (Basel). 2022 Feb 24;14(5):1174.

Inhibiting Glutathione

The treatment protocol incorporates sulfasalazine to enhance ozonide efficacy. While traditionally used as an anti-inflammatory for rheumatoid arthritis and ulcerative colitis, sulfasalazine also inhibits the cystine/glutamate antiporter (system Xc⁻) on tumor cell membranes. This inhibition reduces cystine uptake, an essential precursor for glutathione synthesis, thereby decreasing intracellular glutathione levels in tumor cells. By depleting glutathione, cancer’s primary antioxidant, sulfasalazine renders cancer cells more vulnerable to ozonide-induced oxidative stress.

Reference: Zheng Z, Luo G, Shi X, Long Y, Shen W, Li Z, Zhang X. The X_c^– inhibitor sulfasalazine improves the anti-cancer effect of pharmacological vitamin C in prostate cancer cells via a glutathione-dependent mechanism. Cell Oncol (Dordr). 2020 Feb;43(1):95-106

Note: Sulfasalazine is a medication that contains a sulfonamide group, which can potentially cause an allergic reaction in individuals with a sulfa allergy. In such cases, piperlongumine is used as an alternative.

Inhibiting Thioredoxin

Auranofin, a gold-containing compound initially approved for rheumatoid arthritis treatment, complements ozonide therapy by inhibiting the thioredoxin system, cancer’s secondary antioxidant defense. This disruption of another critical antioxidant pathway further impairs cancer cells’ ability to neutralize excess oxidative stress, promoting tumor cell death.

Reference: Abdalbari FH, Telleria CM. The gold complex auranofin: new perspectives for cancer therapy. Discov Oncol. 2021 Oct 20;12(1):42

Note: If there is an allergy or intolerance to auranofin, gold nanoparticles are used instead.

Inhibiting Nrf2 Activation

Chrysin, a natural compound found in passionflower, can enhance the effective­ness of ROS-mediated cancer treatments by suppressing the Nrf2-mediated antioxi­dant response in cancer cells. Nrf2 is a master regulator that protects cells from oxidative damage by activating antioxidant genes. By inhibiting Nrf2 activation, chrysin prevents cancer cells from adaptively upregulating their antioxidant defenses in response to oxidative stress. This further increases the vulnerability of cancer cells to ROS-induced damage, leading to improved sensitivity to pro-oxidative treat­ments like high-ozonide oil and potentially increased cell death.

Reference: Talebi M, Talebi M, Farkhondeh T, Simal-Gandara J, Kopustinskiene DM, Bernatoniene J, Samarghandian S. Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin. Cancer Cell Int. 2021 Apr 15;21(1):214.

Harnessing Antiparasitic Compounds to Disrupt Multiple Cancer Cell Survival Mechanisms

The final element in enhancing the efficacy of the high-ozonide oil is niclosamide—a medication used to treat tapeworm infections. Niclosamide exhibits multifaceted effects in cancer cells, primarily by increasing ROS and inducing mitochondrial stress, leading to apoptosis. As a mitochondrial uncoupler, niclosamide further disrupts the already altered cardiolipin organization in cancer cell mitochondria, increasing the spreading apart of cardiolipin’s hydrophobic tails and making the mitochondrial membrane even more permeable and susceptible to oxidative damage. This enhanced disruption of cardiolipin structure increases the accessibility of its hydrophobic regions to oxidizing agents like HOO, potentially amplifying its effectiveness. Additionally, niclosamide stimulates autophagy through mTORC1 inhibition, inactivates GSK3β to suppress hedgehog signaling, disrupts Beclin-1/BCL2 interaction to promote autophagic cell death, and induces cell cycle arrest. These mechanisms collectively inhibit cancer cell proliferation, migration, and colony formation. By elevating oxidative stress, destabilizing cardiolipin structure, and modulating multiple signaling pathways, niclosamide may enhance the efficacy of other ROS-inducing anti-cancer therapies like high-ozonide oil.

Note: Standard niclosamide is not used due to its poor bioavailability, which limits its absorption from the gastrointestinal tract into the bloodstream. While this characteristic is advantageous for treating intestinal parasites, it is unsuitable for cancer treatment. Instead, we employ liposomal niclosamide, a formulation that significantly enhances the drug’s absorption and extends its duration of action. This modified version offers superior therapeutic efficacy for cancer treatment.

Reference: Wang Z, Ren J, Du J, Wang H, Liu J, Wang G. Niclosamide as a Promising Therapeutic Player in Human Cancer and Other Diseases. Int J Mol Sci. 2022 Dec 17;23(24):16116.

Synergistic Effects

The synergistic effects of these strategies, all centered around potentiating the action of high-ozonide oil, create a formidable assault on both cancer cells and cancer stem cells. Sulfasalazine inhibits glutathione synthesis, and auranofin disrupts the thioredoxin system, severely compromising the cells’ antioxidant defenses. Chrysin suppresses the Nrf2-mediated antioxidant response, impairing adaptive mechanisms. Concurrently, niclosamide induces mitochondrial stress and promotes autophagy. With these defenses and adaptive mechanisms impaired, cancer cells are left in a precarious state, facing sustained, high levels of ROS generated by the ozonides, which they cannot effectively neutralize.

This multi-faceted approach leads to overwhelming oxidative stress, triggering multiple pathways to cell death, including mitochondrial damage, DNA damage, lipid peroxidation, protein oxidation, and ER stress. The additional stress induced by niclosamide further exacerbates this vulnerability, pushing cancer cells beyond their survival threshold. Importantly, this strategy leverages the inherently higher baseline ROS levels and unique dependencies of cancer cells, potentially offering a degree of selective toxicity. By pushing cancer cells beyond their redox-adaptive capabilities while leaving normal cells’ more robust defense mechanisms relatively intact, this high-ozonide oil-centered therapy presents a promising strategy for effective, targeted, and potentially less toxic cancer treatment.

Complimenting Standard Cancer Treatments

The protocol may enhance their efficacy for chemotherapy, radiotherapy, and targeted therapies by compromising cancer cells’ antioxidant defenses. The high-ozonide oil generates reactive oxygen species, while sulfasalazine inhibits glutathione synthesis and auranofin disrupts the thioredoxin system. Chrysin suppresses the Nrf2-mediated antioxidant response, further impairing adaptive mechanisms. This multi-pronged assault on antioxidant systems could make cancer cells more vulnerable to the oxidative damage caused by chemotherapy and radiotherapy. Niclosamide, which can induce mitochondrial stress and promote autophagy, could synergize with targeted therapies that disrupt specific cellular pathways.

The protocol’s effects on the tumor microenvironment could be particularly relevant for hormone blockade and immunotherapy. Niclosamide has been shown to improve the efficacy of PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer, suggesting it could potentiate immunotherapies. By increasing oxidative stress and altering cellular metabolism, the protocol may also make hormone-dependent cancers more susceptible to hormone blockade therapies. Furthermore, the overall weakening of cancer cells through multiple mechanisms (increased ROS, compromised antioxidant systems, mitochondrial stress) could make them more susceptible to immune-mediated destruction, potentially enhancing the effects of various immunotherapies.

Disclaimer

This information is strictly for educational purposes only and should not be construed as personal medical advice. Do not attempt any cancer treatment on your own. Always consult with a qualified healthcare provider.

Additional References

Auranofin:

1. Cui XY, Park SH, Park WH. Anti-Cancer Effects of Auranofin in Human Lung Cancer Cells by Increasing Intracellular ROS Levels and Depleting GSH Levels. Molecules. 2022 Aug 15;27(16):5207.
2. Cui XY, Park SH, Park WH. Auranofin inhibits the proliferation of lung cancer cells via necrosis and caspase‑dependent apoptosis. Oncol Rep. 2020 Dec;44(6):2715-2724.
3. Fiskus W, Saba N, Shen M, Ghias M, Liu J, Gupta SD, Chauhan L, Rao R, Gunewardena S, Schorno K, Austin CP, Maddocks K, Byrd J, Melnick A, Huang P, Wiestner A, Bhalla KN. Auranofin induces lethal oxidative and endo­plasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia. Cancer Res. 2014 May 1;74(9):2520-32.
4. Gamberi T, Chiappetta G, Fiaschi T, Modesti A, Sorbi F, Magherini F. Upgrade of an old drug: Auranofin in innovative cancer therapies to overcome drug resistance and to increase drug effectiveness. Med Res Rev. 2022 May;42(3):1111-1146.
5. Huang H, Liao Y, Liu N, Hua X, Cai J, Yang C, Long H, Zhao C, Chen X, Lan X, Zang D, Wu J, Li X, Shi X, Wang X, Liu J. Two clinical drugs deubiquiti­nase inhibitor auranofin and aldehyde dehydrogenase inhibitor disulfiram trig­ger synergistic anti-tumor effects in vitro and in vivo. Oncotarget. 2016 Jan 19;7(3):2796-808.
6. Li H, Hu J, Wu S, Wang L, Cao X, Zhang X, Dai B, Cao M, Shao R, Zhang R, Majidi M, Ji L, Heymach JV, Wang M, Pan S, Minna J, Mehran RJ, Swisher SG, Roth JA, Fang B. Auranofin-mediated inhibition of PI3K/AKT/mTOR axis and anticancer activity in non-small cell lung cancer cells. Oncotarget. 2016 Jan 19;7(3):3548-58.
7. Liu X, Wang W, Yin Y, Li M, Li H, Xiang H, Xu A, Mei X, Hong B, Lin W. A high-throughput drug screen identifies auranofin as a potential sensitizer of cisplatin in small cell lung cancer. Invest New Drugs. 2019 Dec;37(6):1166-1176.
8. Nag D, Bhanja P, Riha R, Sanchez-Guerrero G, Kimler BF, Tsue TT, Lominska C, Saha S. Auranofin Protects Intestine against Radiation Injury by Modulating p53/p21 Pathway and Radiosensitizes Human Colon Tumor. Clin Cancer Res. 2019 Aug 1;25(15):4791-4807.
9. Nakaya A, Sagawa M, Muto A, Uchida H, Ikeda Y, Kizaki M. The gold com­pound auranofin induces apoptosis of human multiple myeloma cells through both down-regulation of STAT3 and inhibition of NF-κß activity. Leuk Res. 2011 Feb;35(2):243-9.
10. Park SH, Lee JH, Berek JS, Hu MC. Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53. Int J Oncol. 2014 Oct;45(4):1691-8.
11. Varghese E, Büsselberg D. Auranofin, an anti-rheumatic gold compound, modu­lates apoptosis by elevating the intracellular calcium concentration ([ca2+]I) in mcf-7 breast cancer cells. Cancers (Basel). 2014 Nov 6;6(4):2243-58.
12. Wang H, Bouzakoura S, de Mey S, Jiang H, Law K, Dufait I, Corbet C, Verovski V, Gevaert T, Feron O, Van den Berge D, Storme G, De Ridder M. Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species. Oncotarget. 2017 May 30;8(22):35728-35742.
13. Zou P, Chen M, Ji J, Chen W, Chen X, Ying S, Zhang J, Zhang Z, Liu Z, Yang S, Liang G. Auranofin induces apoptosis by ROS-mediated ER stress and mito­chondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer. Oncotarget. 2015 Nov 3;6(34):36505-21.

Chrysin:

1. Fu B, Xue J, Li Z, Shi X, Jiang BH, Fang J. Chrysin inhibits expression of hypoxia-inducible factor-1alpha through reducing hypoxia-inducible factor-1alpha stability and inhibiting its protein synthesis. Mol Cancer Ther. 2007 Jan;6(1):220-6.
2. Khoo BY, Chua SL, Balaram P. Apoptotic effects of chrysin in human cancer cell lines. Int J Mol Sci. 2010 May 19;11(5):2188-99.
3. Liu X, Zhang X, Shao Z, Zhong X, Ding X, Wu L, Chen J, He P, Cheng Y, Zhu K, Zheng D, Jing J, Luo T. Pyrotinib and chrysin synergistically potentiate autophagy in HER2-positive breast cancer. Signal Transduct Target Ther. 2023 Dec 18;8(1):463.
4. Moghadam ER, Ang HL, Asnaf SE, Zabolian A, Saleki H, Yavari M, Esmaeili H, Zarrabi A, Ashrafizadeh M, Kumar AP. Broad-Spectrum Preclinical Antitumor Activity of Chrysin: Current Trends and Future Perspectives. Biomolecules. 2020 Sep 27;10(10):1374.
5. Raina R, Bhatt R, Hussain A. Chrysin targets aberrant molecular signatures and pathways in carcinogenesis (Review). World Acad Sci J. 2024 Jun;6:45.
6. Salari N, Faraji F, Jafarpour S, Faraji F, Rasoulpoor S, Dokaneheifard S, Mohammadi M. Anti-cancer Activity of Chrysin in Cancer Therapy: a Systematic Review. Indian J Surg Oncol. 2022 Dec;13(4):681-690.
7. Sood A, Mehrotra A, Sharma U, Aggarwal D, Singh T, Shahwan M, Jairoun AA, Rani I, Ramniwas S, Tuli HS, Yadav V, Kumar M. Advancements and recent explorations of anti-cancer activity of chrysin: from molecular targets to therapeutic perspective. Explor Target Antitumor Ther. 2024;5(3):477-494.
8. Tang X, Luo X, Wang X, Zhang Y, Xie J, Niu X, Lu X, Deng X, Xu Z, Wu F. Chrysin Inhibits TAMs-Mediated Autophagy Activation via CDK1/ULK1 Pathway and Reverses TAMs-Mediated Growth-Promoting Effects in Non-Small Cell Lung Cancer. Pharmaceuticals (Basel). 2024 Apr 17;17(4):515.
9. Talebi M, Talebi M, Farkhondeh T, Simal-Gandara J, Kopustinskiene DM, Bernatoniene J, Samarghandian S. Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin. Cancer Cell Int. 2021 Apr 13;21(1):214.

Gold nanoparticles:

1. He JS, Liu SJ, Zhang YR, Chu XD, Lin ZB, Zhao Z, Qiu SH, Guo YG, Ding H, Pan YL, Pan JH. The Application of and Strategy for Gold Nanoparticles in Cancer Immunotherapy. Front Pharmacol. 2021 Jun 7;12:687399.
2. Jain S, Hirst DG, O’Sullivan JM. Gold nanoparticles as novel agents for cancer therapy. Br J Radiol. 2012 Feb;85(1010):101-13.
3. Lim ZZ, Li JE, Ng CT, Yung LY, Bay BH. Gold nanoparticles in cancer therapy. Acta Pharmacol Sin. 2011 Aug;32(8):983-90.
4. Patwardhan RS, Sharma D, Sandur SK. Thioredoxin reductase: An emerging pharmacologic target for radiosensitization of cancer. Transl Oncol. 2022 Mar;17:101341.
5. Penninckx S, Heuskin AC, Michiels C, Lucas S. Thioredoxin Reductase Activity Predicts Gold Nanoparticle Radiosensitization Effect. Nanomaterials (Basel). 2019 Feb 19;9(2):295.
6. Rosa S, Connolly C, Schettino G, Butterworth KT, Prise KM. Biological mechanisms of gold nanoparticle radiosensitization. Cancer Nanotechnol. 2017;8(1):2.

Niclosamide:

1. Cheng B, Morales LD, Zhang Y, Mito S, Tsin A. Niclosamide induces protein ubiquitination and inhibits multiple pro-survival signaling pathways in the human glioblastoma U-87 MG cell line. PLoS One. 2017 Sep 6;12(9):e0184324.
2. Hamdoun S, Jung P, Efferth T. Drug Repurposing of the Anthelmintic Niclosa­mide to Treat Multidrug-Resistant Leukemia. Front Pharmacol. 2017 Mar 10;8:110.
3. Hsu CW, Huang R, Khuc T, Shou D, Bullock J, Grooby S, Griffin S, Zou C, Little A, Astley H, Xia M. Identification of approved and investigational drugs that inhibit hypoxia-inducible factor-1 signaling. Oncotarget. 2016 Feb 16;7(7):8172-83.
4. Huang M, Qiu Q, Zeng S, Xiao Y, Shi M, Zou Y, Ye Y, Liang L, Yang X, Xu H. Niclosamide inhibits the inflammatory and angiogenic activation of human umbilical vein endothelial cells. Inflamm Res. 2015 Dec;64(12):1023-32.
5. Jeengar MK, Kumar S, Shrivastava S, P SN et al. Niclosamide exerts anti-tumor activity through generation of reactive oxygen species and by sup­pression of Wnt/ β-catenin signaling axis in HGC-27, MKN-74 human gas­tric cancer cells. Asia-Pac J Oncol 2020.
6. Jiang H, Li AM, Ye J. The magic bullet: Niclosamide. Front Oncol. 2022 Nov 21;12:1004978.
7. Jin Y, Lu Z, Ding K, Li J, Du X, Chen C, Sun X, Wu Y, Zhou J, Pan J. Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: inactivation of the NF-kappaB pathway and generation of reac­tive oxygen species. Cancer Res. 2010 Mar 15;70(6):2516-27.
8. Kaushal JB, Bhatia R, Kanchan RK, Raut P, Mallapragada S, Ly QP, Batra SK, Rachagani S. Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3β. Cancers (Basel). 2021 Jun 22;13(13):3105.
9. Kulthawatsiri T, Kittirat Y, Phetcharaburanin J, Tomacha J, Promraksa B, Wangwiwatsin A, Klanrit P, Titapun A, Loilome W, Namwat N. Metabo­lomic analyses uncover an inhibitory effect of niclosamide on mitochondrial membrane potential in cholangiocarcinoma cells. PeerJ. 2023 Nov 22;11:e16512.
10. Kumar R, Coronel L, Somalanka B, Raju A, Aning OA, An O, Ho YS, Chen S, Mak SY, Hor PY, Yang H, Lakshmanan M, Itoh H, Tan SY, Lim YK, Wong APC, Chew SH, Huynh TH, Goh BC, Lim CY, Tergaonkar V, Cheok CF. Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers. Nat Commun. 2018 Sep 26;9(1):3931.
11. Lee MC, Chen YK, Hsu YJ, Lin BR. Niclosamide inhibits the cell prolifera­tion and enhances the responsiveness of esophageal cancer cells to chemo­therapeutic agents. Oncol Rep. 2020 Feb;43(2):549-561.
12. Li Y, Li PK, Roberts MJ, Arend RC, Samant RS, Buchsbaum DJ. Multi-tar­geted therapy of cancer by niclosamide: A new application for an old drug. Cancer Lett. 2014 Jul 10;349(1):8-14.
13. Lu L, Dong J, Wang L, Xia Q, Zhang D, Kim H, Yin T, Fan S, Shen Q. Acti­vation of STAT3 and Bcl-2 and reduction of reactive oxygen species (ROS) promote radioresistance in breast cancer and overcome of radioresistance with niclosamide. Oncogene. 2018 Sep;37(39):5292-5304.
14. Lu W, Lin C, Roberts MJ, Waud WR, Piazza GA, Li Y. Niclosamide sup­presses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/β-catenin pathway. PLoS One. 2011;6(12):e29290.
15. Luo F, Luo M, Rong QX, Zhang H, Chen Z, Wang F, Zhao HY, Fu LW. Niclosamide, an antihelmintic drug, enhances efficacy of PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer. J Immunother Cancer. 2019 Sep 11;7(1):245.
16. Mathew M, Sivaprakasam S, Dharmalingam-Nandagopal G, Sennoune SR, Nguyen NT, Jaramillo-Martinez V, Bhutia YD, Ganapathy V. Induction of Oxidative Stress and Ferroptosis in Triple-Negative Breast Cancer Cells by Niclosamide via Blockade of the Function and Expression of SLC38A5 and SLC7A11. Antioxidants (Basel). 2024 Feb 27;13(3):291.
17. Mito S, Cheng B, Garcia BA, Yee Ooi X, Gonzalez D, Ruiz TC, Elisarraras FX, Tsin A. SAR study of niclosamide derivatives for neuroprotective func­tion in SH-SY5Y neuroblastoma. Bioorg Med Chem Lett. 2023 Nov 15;96:129498.
18. Pan JX, Ding K, Wang CY. Niclosamide, an old antihelminthic agent, demonstrates antitumor activity by blocking multiple signaling pathways of cancer stem cells. Chinese Journal of Cancer. 2012 Apr;31(4):178-184.
19. Ren J, Wang B, Wu Q, Wang G. Combination of niclosamide and current therapies to overcome resistance for cancer: New frontiers for an old drug. Biomed Pharmacother. 2022 Nov;155:113789.
20. Sennoune SR, Nandagopal GD, Ramachandran S, Mathew M, Sivaprakasam S, Jaramillo-Martinez V, Bhutia YD, Ganapathy V. Potent Inhibition of Macropinocytosis by Niclosamide in Cancer Cells: A Novel Mechanism for the Anticancer Efficacy for the Antihelminthic. Cancers (Basel). 2023 Jan 26;15(3):759.
21. Shangguan F, Liu Y, Ma L, Qu G, Lv Q, An J, Yang S, Lu B, Cao Q. Niclos­amide inhibits ovarian carcinoma growth by interrupting cellular bioenerget­ics. J Cancer. 2020 Mar 13;11(12):3454-3466.
22. Suliman MA, Zhang Z, Na H, Ribeiro AL, Zhang Y, Niang B, Hamid AS, Zhang H, Xu L, Zuo Y. Niclosamide inhibits colon cancer progression through downregulation of the Notch pathway and upregulation of the tumor suppressor miR-200 family. Int J Mol Med. 2016 Sep;38(3):776-84.
23. Tanaka T, Asano T, Okui T, Kuraoka S, Singh SA, Aikawa M, Aikawa E. Computational Screening Strategy for Drug Repurposing Identified Niclosamide as Inhibitor of Vascular Calcification. Front Cardiovasc Med. 2022 Jan 20;8:826529.
24. Wang C, Zhou X, Xu H, Shi X, Zhao J, Yang M, Zhang L, Jin X, Hu Y, Li X, Xiao X, Liao M. Niclosamide Inhibits Cell Growth and Enhances Drug Sensitivity of Hepatocellular Carcinoma Cells via STAT3 Signaling Path­way. J Cancer. 2018 Oct 18;9(22):4150-4155.
25. Wang LH, Xu M, Fu LQ, Chen XY, Yang F. The Antihelminthic Niclosa­mide Inhibits Cancer Stemness, Extracellular Matrix Remodeling, and Metastasis through Dysregulation of the Nuclear β-catenin/c-Myc axis in OSCC. Sci Rep. 2018 Aug 24;8(1):12776.
26. Wang YC, Chao TK, Chang CC, Yo YT, Yu MH, Lai HC. Drug screening identifies niclosamide as an inhibitor of breast cancer stem-like cells. PLoS One. 2013 Sep 18;8(9):e74538.
27. Xiang M, Chen Z, Yang D, Li H, Zuo Y, Li J, Zhang W, Zhou H, Jiang D, Xu Z, Yu Z. Niclosamide enhances the antitumor effects of radiation by inhibiting the hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway in human lung cancer cells. Oncol Lett. 2017 Aug;14(2):1933-1938.
28. Yeh LT, Lin CW, Lu KH, Hsieh YH, Yeh CB, Yang SF, Yang JS. Niclosa­mide Suppresses Migration and Invasion of Human Osteosarcoma Cells by Repressing TGFBI Expression via the ERK Signaling Pathway. Int J Mol Sci. 2022 Jan 1;23(1):484.
29. Zhang Q, Yang Z, Hao X, Dandreo LJ, He L, Zhang Y, Wang F, Wu X, Xu L. Niclosamide improves cancer immunotherapy by modulating RNA-binding protein HuR-mediated PD-L1 signaling. Cell Biosci. 2023 Oct 17;13(1):192.

Ozone:

1. Baeza-Noci J, Pinto-Bonilla R. Systemic Review: Ozone: A Potential New Chemotherapy. Int J Mol Sci. 2021 Oct 30;22(21):11796.
2. Li Y, Pu R. Ozone Therapy for Breast Cancer: An Integrative Literature Review. Integr Cancer Ther. 2024 Jan-Dec;23:15347354241226667.

Piperlongumine:

1. Chen W, Lian W, Yuan Y, Li M. The synergistic effects of oxaliplatin and piperlongumine on colorectal cancer are mediated by oxidative stress. Cell Death Dis. 2019 Aug 8;10(8):600.
2. Chen YJ, Kuo CC, Ting LL, Lu LS, Lu YC, Cheng AJ, Lin YT, Chen CH, Tsai JT, Chiou JF. Piperlongumine inhibits cancer stem cell properties and regulates multiple malignant phenotypes in oral cancer. Oncol Lett. 2018 Feb;15(2):1789-1798.
3. Dhillon H, Chikara S, Reindl KM. Piperlongumine induces pancreatic cancer cell death by enhancing reactive oxygen species and DNA damage. Toxicol Rep. 2014;1:309-318.
4. Kung FP, Lim YP, Chao WY, Zhang YS, Yu HI, Tai TS, Lu CH, Chen SH, Li YZ, Zhao PW, Yen YP, Lee YR. Piperlongumine, a Potent Anticancer Phyto­therapeutic, Induces Cell Cycle Arrest and Apoptosis In Vitro and In Vivo through the ROS/Akt Pathway in Human Thyroid Cancer Cells. Cancers (Basel). 2021 Aug 24;13(17):4266.
5. Li J, Sharkey CC, King MR. Piperlongumine and immune cytokine TRAIL synergize to promote tumor death. Sci Rep. 2015 May 18;5:9987.
6. Lin TH, Kuo CH, Zhang YS, Chen PT, Chen SH, Li YZ, Lee YR. Piper­longumine Induces Cellular Apoptosis and Autophagy via the ROS/Akt Sig­naling Pathway in Human Follicular Thyroid Cancer Cells. Int J Mol Sci. 2023 Apr 28;24(9):8048.
7. Liu F, Zhou Q, Jiang Hf. et al. Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblas­toma via boosting oxidative stress-inflamation-CD8⁺-T cell immunity. J Exp Clin Cancer Res 42, 118 (2023).
8. Lu X, Xu C, Xu Z, Lu C, Yang R, Zhang F, Zhang G. Piperlongumine inhib­its the growth of non-small cell lung cancer cells via the miR-34b-3p/TGFBR1 pathway. BMC Complement Med Ther. 2021 Jan 7;21(1):15.
9. Parama D, Rana V, Girisa S, Verma E, Daimary UD, Thakur KK, Kumar A, Kunnumakkara AB. The promising potential of piperlongumine as an emerg­ing therapeutics for cancer. Explor Target Antitumor Ther. 2021;2(4):323-354.
10. Parveen S, Kumar S, Pal S, Yadav NP, Rajawat J, Banerjee M. Enhanced therapeutic efficacy of Piperlongumine for cancer treatment using nano-lipo­somes mediated delivery. Int J Pharm. 2023 Aug 25;643:123212.
11. Roh JL, Kim EH, Park JY, Kim JW, Kwon M, Lee BH. Piperlongumine selectively kills cancer cells and increases cisplatin antitumor activity in head and neck cancer. Oncotarget. 2014 Oct 15;5(19):9227-38.
12. Tripathi SK, Biswal BK. Piperlongumine, a potent anticancer phytothera­peutic: Perspectives on contemporary status and future possibilities as an anticancer agent. Pharmacol Res. 2020 Jun;156:104772.
13. Wang H, Jiang H, Corbet C, de Mey S, Law K, Gevaert T, Feron O, De Ridder M. Piperlongumine increases sensitivity of colorectal cancer cells to radiation: Involvement of ROS production via dual inhibition of glutathione and thioredoxin systems. Cancer Lett. 2019 May 28;450:42-52.
14. Wang Y, Wang JW, Xiao X, Shan Y, Xue B, Jiang G, He Q, Chen J, Xu HG, Zhao RX, Werle KD, Cui R, Liang J, Li YL, Xu ZX. Piperlongumine induces autophagy by targeting p38 signaling. Cell Death Dis. 2013 Oct 3;4(10):e824.
15. Wang ZQ, Li YQ, Wang DY, Shen YQ. Natural product piperlongumine inhibits proliferation of oral squamous carcinoma cells by inducing ferroptosis and inhibiting intracellular antioxidant capacity. Transl Cancer Res. 2023 Oct 31;12(10):2911-2922.
16. Zhang Q, Chen W, Lv X, Weng Q, Chen M, Cui R, Liang G, Ji J. Piper­longumine, a Novel TrxR1 Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cells by ROS-Mediated ER Stress. Front Pharmacol. 2019 Oct 14;10:1180.

Sulfasalazine:

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