By Troy Valencia

Blog Recap

Sigma receptors, particularly sigma-2 (σ2), are emerging as key targets in cancer therapy due to their overexpression in proliferating tumor cells and involvement in critical cellular processes such as endoplasmic reticulum (ER) stress, calcium signaling, and apoptosis. Ibogaine, a psychoactive alkaloid, has shown selective binding to σ2 receptors, offering a novel therapeutic approach to cancer treatment. This paper synthesizes findings from multiple studies to explore ibogaine’s potential as a cancer therapy, focusing on its mechanisms of action through σ2 receptor binding. The paper highlights cancers overexpressing sigma receptors, including breast, lung, and ovarian cancers, and discusses the use of sigma receptor ligands in drug delivery and apoptosis induction. Additionally, challenges in ibogaine’s clinical application and the need for developing derivatives with enhanced specificity and reduced toxicity are addressed. By integrating the latest research, this paper underscores ibogaine’s promise in targeting σ2 receptors to disrupt cancer cell homeostasis and improve therapeutic outcomes.

Introduction

Sigma receptors, classified into sigma-1 (σ1) and sigma-2 (σ2) subtypes, are involved in various physiological and pathological processes, including ER stress, calcium signaling, and mitochondrial integrity (Tesei et al., 2018). Overexpression of these receptors in cancer cells has led to their recognition as valuable therapeutic targets. Notably, σ2 receptors are overexpressed in proliferating tumors and are implicated in pathways regulating cell survival and apoptosis. Ibogaine, a natural alkaloid with known psychoactive properties, exhibits selective binding to σ2 receptors, making it a promising candidate for cancer therapy (Floresta et al., 2019). This paper examines ibogaine’s potential in targeting σ2 receptors for cancer treatment, focusing on breast, lung, and ovarian cancers exhibiting sigma receptor over expression.

Sigma Receptors and Cancer

Think of sigma receptors as tiny “control hubs” in cells, especially in cancer cells. These hubs help cancer cells manage stress, repair damage and survive harsh conditions like low oxygen or lack of nutrients. They’re often found in large numbers (overexpressed) in cancer cells, making them essential for the tumor’s survival and growth. Cancer cells are like factories working overtime. This creates stress inside the cell, especially in the part called the endoplasmic reticulum (ER), which manages protein folding and other cell activities. Sigma receptors, especially the sigma-2 type, act like “stress managers,” helping the cancer cells handle this chaos and stay alive.

Sigma receptors play a crucial role in cancer biology by modulating ER stress and signaling pathways essential for tumor cell survival. The σ1 receptor is predominantly localized at ER-mitochondria-associated membranes (MAMs), regulating calcium signaling, protein folding, and mitochondrial function. Overexpression of σ1 has been associated with aggressive breast cancer phenotypes, including triple-negative breast cancer, which lacks effective targeted therapies (Robinson & Osman, 2023). Similarly, σ2 receptors are highly expressed in proliferating cancer cells, including ovarian and lung cancers, and are considered biomarkers for tumor proliferation (Zeng et al., 2013; Ezhilarasan et al., 2022).

Ibogaine and Sigma-2 Receptors

Iboga contains a compound called ibogaine, which can bind to these sigma-2 receptors. When ibogaine attaches to these receptors, it “disrupts” their work. This means:

• The cancer cell’s stress management system breaks down.
• The cancer cell can’t handle all the chaos inside, leading to cell death (apoptosis).
• By targeting sigma receptors, ibogaine makes it harder for cancer cells to survive and multiply.

Why is Iboga special?

Ibogaine is selective—it targets the sigma-2 receptors that are more common in cancer cells than in normal cells. This gives it a better chance of attacking cancer while leaving healthy cells less affected. Ibogaine demonstrates selective binding to σ2 receptors, with its interaction disrupting cellular homeostasis in cancer cells (Floresta et al., 2019). This binding interferes with the σ2 receptor’s role in regulating ER stress responses, a critical survival mechanism for cancer cells under unfavorable conditions such as hypoxia and nutrient deprivation (Tesei et al., 2018). By targeting σ2 receptors, ibogaine can induce apoptotic pathways, destabilizing cancer cells’ ability to manage stress effectively.

Therapeutic Applications Across Cancer Types

Ibogaine’s action on sigma receptors is especially promising for cancers like:

1. Breast cancer, including aggressive types like triple-negative.
2. Lung cancer, where sigma receptors can help improve drug delivery.
3. Ovarian cancer, by using sigma receptors to deliver powerful, targeted therapies.
4. Breast Cancer
   Sigma-1 receptors are implicated in calcium signaling and ER stress regulation, processes critical for the survival of aggressive breast cancers, including triple-negative subtypes. Modulating σ1 and σ2 receptor activity can enhance apoptosis and inhibit tumor growth, making sigma receptor ligands promising therapeutic agents for breast cancer (Robinson & Osman, 2023).
5. Lung Cancer
   Lung cancer is characterized by high mortality due to ineffective drug delivery and significant side effects. Targeting sigma receptors using nanoparticle systems has shown promise in enhancing drug delivery specificity and efficacy. Sigma-targeted nanoparticles improve bioavailability and reduce off-target effects, providing a model for ibogaine-based therapies in lung cancer (Ezhilarasan et al., 2022).
6. Ovarian Cancer
   Sigma-2 receptors have been successfully targeted in ovarian cancer to deliver therapeutic agents such as SMAC mimetics, activating intrinsic and extrinsic apoptotic pathways. This approach exemplifies the potential of σ2 ligands, including ibogaine, to deliver cytotoxic agents effectively and induce tumor cell death (Zeng et al., 2013).

Mechanisms of Action

1. ER Stress and Apoptosis
   Sigma receptors act as gatekeepers of ER stress, regulating protein folding and calcium homeostasis. Targeting these receptors can disrupt cancer cells’ ability to adapt to stress, leading to apoptosis. Ibogaine’s binding to σ2 receptors triggers apoptotic pathways by destabilizing ER stress management systems (Tesei et al., 2018).
2. Drug Delivery and Targeting
   Sigma receptors serve as effective targets for delivering anticancer agents. Nanoparticles targeting σ2 receptors have been used to deliver therapeutic drugs directly to tumor cells, enhancing efficacy while minimizing systemic toxicity. Ibogaine-based formulations could benefit from similar delivery mechanisms (Ezhilarasan et al., 2022).
3. Proliferation and Survival Pathways
   Sigma receptors modulate signaling pathways such as NF-κB, influencing tumor proliferation and survival. By binding to σ2 receptors, ibogaine could inhibit these pathways, reducing cancer cell viability and promoting cell death (Zeng et al., 2013).

Challenges and Future Directions

While ibogaine’s affinity for σ2 receptors is promising, its psychoactive properties and associated toxicities limit its direct clinical application (Floresta et al., 2019). Developing ibogaine derivatives with enhanced specificity and reduced side effects is essential. Further research is needed to elucidate sigma receptors’ structural and functional roles in different cancer types, which could optimize therapeutic strategies and pave the way for ibogaine’s clinical use (Tesei et al., 2018).

Conclusion

The big picture:
By binding to sigma-2 receptors, ibogaine disrupts the cancer cell’s stress response, pushing it toward death and making it harder for the tumor to grow or spread. Scientists are now exploring ways to make ibogaine or similar compounds safer and more effective for cancer treatment

Ibogaine’s selective binding to σ2 receptors represents a novel approach to cancer therapy by targeting mechanisms essential for tumor survival, including ER stress regulation and apoptotic pathways. The overexpression of sigma receptors in breast, lung, and ovarian cancers highlights their relevance as therapeutic targets. While challenges remain in translating ibogaine’s properties into clinical applications, ongoing research into sigma receptor biology and ibogaine derivatives holds promise for developing effective cancer treatments.

By: Troy M. Valencia, Founder of Root & Wisdom, Clinical Psychology Doctoral Student

Contact:

Email: Troy@rootandwisdom.com

Website: www.rootandwisdom.com (Iboga retreats)

Website: www.authentic-empowerment.com (Coaching Platform)

Website: www.sacredrootsfoundation.com (non-profit)

References

Ezhilarasan, D., Lakshmi, T., & Mallineni, S. K. (2022). Nano-based targeted drug delivery for lung cancer: Therapeutic avenues and challenges. Nanomedicine (London, England), 17(24), 1855–1869. https://doi.org/10.2217/nnm-2021-0364

Floresta, G., Dichiara, M., Gentile, D., Prezzavento, O., Marrazzo, A., Rescifina, A., & Amata, E. (2019). Morphing of Ibogaine: A Successful Attempt into the Search for Sigma-2 Receptor Ligands. International Journal of Molecular Sciences, 20(3), 488. https://doi.org/10.3390/ijms20030488

Robinson, T. S., & Osman, M. A. (2023). An Emerging Role for Sigma Receptor 1 in Personalized Treatment of Breast Cancer. Cancers, 15(13), 3464. https://doi.org/10.3390/cancers15133464

Tesei, A., Cortesi, M., Zamagni, A., Arienti, C., Pignatta, S., Zanoni, M., Paolillo, M., Curti, D., Rui, M., Rossi, D., & Collina, S. (2018). Sigma Receptors as Endoplasmic Reticulum Stress “Gatekeepers” and their Modulators as Emerging New Weapons in the Fight Against Cancer. Frontiers in Pharmacology, 9, 711. https://doi.org/10.3389/fphar.2018.00711

Zeng, C., Vangveravong, S., McDunn, J. E., Hawkins, W. G., & Mach, R. H. (2013). Sigma-2 receptor ligand as a novel method for delivering a SMAC mimetic drug for treating ovarian cancer. British Journal of Cancer, 109(9), 2368–2377. https://doi.org/10.1038/bjc.2013.593