Antidepressants could potentially be repurposed as anticancer agents based on emerging evidence showing they can modulate autophagy—a process cancer cells rely on for growth and survival.
Key Facts:
- Many antidepressants like SSRIs and TCAs have demonstrated anticancer effects in lab studies. Their mechanisms involve regulating autophagy, which plays a complex role in cancer development.
- Specific antidepressants can either induce autophagy to promote cancer cell death or inhibit autophagy to cut off a protective pathway tumors exploit.
- Combining antidepressants with other chemotherapy drugs has shown enhanced antitumor activity, overcoming resistance issues seen with standard treatments.
- More clinical trials are underway to evaluate whether the promising anticancer effects of antidepressants observed in cell cultures and animals can translate to improved outcomes for cancer patients.
Source: Molecules (2023)
The Growing Promise of Repurposed Drugs
Cancer remains one of the world’s most pressing health issues, responsible for nearly 10 million deaths globally in 2020.
As researchers urgently seek new therapeutic angles of attack against this devastating disease, increasing attention has turned toward repurposing—finding novel medical applications for drugs already approved to treat other conditions.
Rather than developing agents from scratch, which is extremely costly and time-intensive, repurposing allows existing medications with known safety profiles in humans to progress more rapidly through the drug development pipeline.
One class of repurposed drugs sparking interest as anticancer agents is perhaps unexpected: antidepressants.
How Do Antidepressants Inhibit Cancer Growth?
Many types of antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and tricyclic medications (TCAs) like imipramine, have exhibited antitumor effects in preclinical studies across a range of cancer models.
Significantly, their anticancer mechanisms appear closely tied to modulating autophagy.
Autophagy’s Complex Role in Cancer
Autophagy is a cellular recycling process that allows cells to break down and reuse damaged cell parts and molecules, helping them survive periods of stress.
This process plays a complex, context-dependent role in cancer.
On one hand, autophagy can suppress early-stage tumor growth by removing damaged proteins and organelles before they spark uncontrolled cell proliferation.
However, advanced cancers often become reliant on elevated autophagy activity to fuel their rapid expansion and withstand nutrient limitation or hypoxia inside growing tumor masses.
Antidepressants as Autophagy Modulators
By regulating different aspects of the autophagy pathway, antidepressants can either coax cancer cells to “self-eat” themselves via excess autophagy or cut off autophagy support tumors depend upon:
Inducing Autophagy
- Imipramine, desipramine, fluoxetine and others trigger autophagosome formation by inhibiting mTOR signaling or activating AMPK, critical cellular regulators of autophagy.
- Sustained, uncontrolled autophagy induction leads cancer cells to essentially digest themselves.
Blocking Autophagy
- Sertraline, paroxetine, and additional antidepressants disrupt late-stage autophagy by preventing fusion of autophagosomes with lysosomes.
- This inhibition causes toxic buildup of cellular junk that tumors rely on autophagy to eliminate.
Combining Antidepressants with Chemotherapy Drugs
Notably, combining antidepressants with other chemotherapy agents has yielded synergistic responses in laboratory cancer models, enhancing cytotoxic effects.
The studies indicate lower doses of both drugs can be used to reduce side effects while overcoming resistance issues seen with standard regimens alone.
Select examples demonstrating improved antitumor activity when pairing antidepressants with other agents:
- Fluoxetine + Raloxifene (breast cancer)
- Imipramine + Temozolomide (glioblastoma brain tumor)
- Sertraline + Erlotinib (non-small cell lung cancer)
Moving Toward Clinical Applications
Despite initially promising results from preclinical work, substantial research is still needed to evaluate whether antidepressants’ anticancer properties translate from laboratory models to actual patients.
However, early-phase clinical trials testing their safety and efficacy as therapeutics for cancers like glioblastoma and breast tumors are now underway.
Repurposing common antidepressants as autophagy-targeting weapons against cancer represents an appealing drug development approach given these agents’:
- Established human safety data
- Ability to enhance chemotherapy sensitivity
- Potential to overcome treatment resistance
If clinical evaluations demonstrate improved patient outcomes with acceptable toxicity profiles, antidepressant drug repurposing could unlock simple, widely accessible new tools in the anticancer arsenal.
Mechanistic Insights Into Antidepressants As Autophagy Modulators
While anticancer effects have been demonstrated for antidepressants spanning multiple drug classes, their specific mechanisms regulating autophagy differ substantially.
Elucidating how distinct agents interface with the highly complex autophagy pathway will be key to strategically targeting tumors’ reliance on this process.
Deciphering Autophagy Signaling
Autophagy encompasses several interdependent stages.
First, double-membrane vesicles called autophagosomes take shape and encapsulate cellular contents marked for degradation.
Autophagosomes then fuse with lysosomes whose digestive enzymes break down and recycle the autophagic cargo.
The autophagy pathway includes two key nodes antidepressants appear capable of modulating to push cancer cells past their breaking point:
- Early Stage: Regulating autophagosome formation
- Late Stage: Controlling autophagosome-lysosome fusion
Master regulator mTOR restrains autophagy induction under nutrient-rich conditions while AMPK triggers the catabolic process when cellular energy is low.
Antidepressants like fluoxetine can hijack these critical signaling proteins to override cancer cells’ normal autophagy brakes.
Alternatively, agents like paroxetine disrupt the final stage by preventing proper autophagosome-lysosome fusion.
This ineffective autophagy causes toxic intermediates to accumulate, denying tumors an essential survival outlet.
Spotlight on Specific Antidepressants
Diverse antidepressants impact discrete aspects of the intricate autophagy signaling web to undermine cancer growth.
Highlighted below are key examples that have garnered particular research interest:
Imipramine
- Mechanism: Inhibits Akt/mTOR pathway to induce uncontrolled autophagy
- Cancer models: Glioblastoma, lung cancer
Desipramine
- Mechanism: Triggers ER stress response to activate pro-autophagic PERK signaling
- Cancer models: Glioma
Fluoxetine
- Mechanism: Activates AMPK while suppressing mTOR and eEF2K to drive autophagosome formation
- Cancer models: Breast cancer, Burkitt’s lymphoma
Paroxetine
- Mechanism: Disrupts lysosome acidification, preventing autophagosome clearance
- Cancer models: Lung cancer
While many mysteries around antidepressants’ autophagy modulating functions remain, unraveling their precise modes of action should open new possibilities for therapeutic intervention against stubborn malignancies.
Augmented Chemotherapy Responses
In addition to direct antitumor activity when applied as single agents, another compelling aspect of antidepressants is their ability to enhance cancer sensitivity to standard chemotherapy medications.
Laboratory investigations indicate combining antidepressants with cytotoxic or targeted therapies not only improves tumor cell killing, but allows lower, safer drug doses to be administered—attenuating problematic side effects of conventional regimens.
Chemosensitization Effects
Notable positive interactions yielding augmented anticancer responses when pairing antidepressants with other agents include:
- Clomipramine increased cervical cancer susceptibility to cisplatin
- Desipramine strengthened cytotoxicity of platinum drugs in breast cancer models
- Fluoxetine added to paclitaxel intensified apoptosis in prostate tumors
- Sertraline re-sensitized non-small cell lung cancers resistant to erlotinib
The capability to reverse chemoresistance suggests incorporating selected antidepressants could provide clinical benefit when standard therapies lose effectiveness.
Enhanced Antitumor Immunity
Alongside direct cancer cell-killing synergism, emerging evidence also indicates combining antidepressants with immune-stimulating therapies may elicit greater therapeutic responses by more fully activating anticancer immune activity.
For example, co-administering imipramine alongside an anti-VEGF antibody was found to not only stall glioblastoma growth through increased autophagy induction, but also stimulated infiltration of T cells responsible for antitumor immunity.
The immune-enhancing effects were dependent on functional autophagy signaling, again underscoring antidepressants’ autophagy modulating mechanisms as central to their anticancer utility.
Ongoing Clinical Evaluations
Despite antidepressants’ promise suggested by preclinical experiments,confirmation of actual treatment benefits for cancer patients awaits results from human clinical trials.
So far, early safety-focused studies pairing antidepressants with standard chemotherapy regimens have launched.
Select active or upcoming Phase I/II human trials include:
- Imipramine + temozolomide (recurrent glioblastoma)
- Desipramine (small cell lung cancer)
- Maprotiline + tamoxifen + temozolomide (recurrent glioblastoma)
- Fluoxetine + chemotherapy (non-small cell lung cancer)
Outcomes data evaluating whether anticancer signals observed with antidepressants in laboratory models translate to improved patient responses remain incomplete.
Still, demonstration of acceptable toxicity profiles would support conducting more expansive late-stage testing of their therapeutic potential.
Future Opportunities And Challenges
Repurposing common antidepressants like SSRIs and TCAs to treat cancer represents an appealing drug development proposition offering:
- Established human safety information
- Rapid advancement to clinical testing stages
- Lower costs compared to new molecular entity development
However, key challenges must still be addressed before anticancer applications of antidepressants can be responsibly translated into widespread patient use.
Resolving Therapeutic Tradeoffs
If their autophagy-modulating mechanisms prove efficacious against cancer in clinical practice, deciding which patient groups would derive greatest benefit while balancing side effect risks will require clarification.
Could hazards emerge from overly suppressing or activating autophagy essential for normal cell health in certain tissues?
As research progresses, treatment regimens incorporating antidepressants will likely need customization based on cancer genetics and stage, along with the health status of individual patients.
Overcoming Antagonistic Drug Interactions
Since antidepressants taken for their psychiatric indications already interact with molecules metabolized by the cytochrome P450 enzyme system, concomitant effects when combined with chemotherapies also utilizing this same pathway must be scrutinized to avoid reductions in anticancer efficacy or enhanced toxicity.
Monitoring for reduced effectiveness or heightened adverse reactions will be imperative in active clinical trials, informing safe antidepressant-chemo coadministration guidelines.
The Way Forward
While substantial research remains to validate early encouraging signals, repurposing common antidepressants like Prozac or Elavil to combat malignancies could open new, inexpensive therapeutic avenues benefiting cancer patients worldwide.
This is especially true if synergistic interactions with current chemotherapies also enable lowering cytotoxic drug doses to attenuate their harsh side effects.
Given autophagy supports progression of numerous aggressive and drug-resistant tumors, scrutinizing how different antidepressants interface with this pathway may uncover fresh tactical opportunities to finally outmaneuver these challenging diseases.
References
- Study: Antidepressants as autophagy modulators for cancer therapy
- Authors: Leping He et al. (2023)
