# Natural bioactive molecules and chemotherapeutics synergism for enhanced cancer therapy

## TL;DR

This paper reviews how natural compounds can work with chemotherapy to improve cancer treatment by boosting effectiveness and reducing side effects.

## Contribution

The paper systematically reviews mechanisms and evidence for natural bioactives as adjuvants to chemotherapy, highlighting their dual role in enhancing efficacy and reducing toxicity.

## Key findings

- Natural bioactives modulate pathways like NF-κB and PI3K/AKT/mTOR to enhance chemotherapy efficacy and overcome resistance.
- Combinations like curcumin with 5-fluorouracil show improved antitumor activity and reduced toxicity in preclinical models.
- Natural compounds also protect against chemotherapy-induced organ toxicities such as cardiotoxicity and nephrotoxicity.

## Abstract

Chemotherapy remains a foundation of cancer care but is limited by multidrug resistance, systemic toxicities, and suboptimal selectivity, prompting interest in adjunctive strategies that improve efficacy and tolerability without adding significant burden to patients or healthcare systems.

This review highlights evidence on natural bioactive compounds, including polyphenols, alkaloids, terpenoids, and fungal metabolites, as adjuvants to standard chemotherapeutics, with objectives to: first, delineate mechanisms by which these agents enhance cytotoxic efficacy and overcome resistance; second, summarize preclinical and clinical combination data; and third, evaluate their potential to mitigate chemotherapy-induced organ toxicities through pathway modulation.

Natural bioactives modulate key oncogenic and stress-response pathways, such as NF-κB, PI3K/AKT/mTOR, and NRF2/HO-1, thereby sensitizing tumors to chemotherapy, attenuating pro-survival signaling, and enhancing apoptosis while reducing inflammatory and oxidative injury in normal tissues. Exemplary combinations, including curcumin with 5‑fluorouracil and resveratrol with cisplatin, have demonstrated improved antitumor activity and reduced toxicity in preclinical models, with early clinical observations supporting feasibility and safety in selected settings. Additionally, several compounds exhibit organ-protective effects against cardiotoxicity, nephrotoxicity, neurotoxicity, and gastrointestinal injury induced by chemotherapy, suggesting dual benefits on efficacy and tolerability profiles.

Integrating natural bioactives with conventional chemotherapy represents a promising strategy to enhance therapeutic index by concurrently amplifying antitumor mechanisms and mitigating dose‑limiting toxicities, though broader clinical validation and standardized quality controls are needed for routine adoption.

•Cancer incidence and mortality rates are rising worldwide, posing significant public health challenges

•Chemotherapy remains the primary treatment despite tumor resistance and severe patient side effects.

•Combination therapies targeting multiple pathways improve efficacy and reduce harmful chemotherapy side effects.