# Captivating Synergistic, Dose-Dependent Anticancer Effects of Tumor-Regulation Modulators Chloroquine and Ivermectin Completely Abolished by an Opposing Modulator, Deoxycholic Acid, in Hamster Fibrosarcoma: In Vivo, In Vitro, and Literature Review

## TL;DR

Chloroquine and ivermectin together show strong anticancer effects in hamsters, but these effects are canceled out by deoxycholic acid.

## Contribution

A synergistic, non-toxic combination of chloroquine and ivermectin is shown to suppress fibrosarcoma, with reversal by deoxycholic acid.

## Key findings

- Chloroquine and ivermectin combination showed dose-dependent anticancer effects in hamsters and human cancer cell lines.
- Deoxycholic acid reversed the anticancer effects of the drug combination.
- The drug combination was non-toxic at effective doses.

## Abstract

Background/Objectives: In previous studies, chloroquine and ivermectin separately exhibited similar anticancer effects on various known cancer modulatory targets. This study aimed (1) to identify a non-toxic synergistic combination of chloroquine and ivermectin that suppresses hamster fibrosarcoma; (2) to verify combined antitumor efficacy using dose–response analysis; and (3) to investigate potential synergistic mechanisms by restoring tumor progression with the reciprocal cancer-modulating agent deoxycholic acid. Methods: A BHK-21/C13 cell culture was subcutaneously inoculated into Syrian golden hamsters randomly divided into groups (6 animals per group): (1) untreated control; treated daily (17 days after inoculation) with (2) chloroquine 50 mg/kg; (3) ivermectin 5 mg/kg; (4) a combination of chloroquine 50 mg/kg and ivermectin 5 mg/kg; (5) a combination of chloroquine 50 mg/kg, ivermectin 5 mg/kg and deoxycholic acid 100 mg/kg; (6) a combination of chloroquine 25 mg/kg and ivermectin 2.5 mg/kg; (7) a combination of chloroquine 12.5 mg/kg and ivermectin 1.25 mg/kg. Dose–response curves were generated for chloroquine and ivermectin combinations. Characteristics of tumors (growth kinetics, biophysical, histological, immunohistochemical, pathological), hamster organs, biochemical and hematological blood tests were compared among the groups. Results: The synergistic, dose-dependent anticancer effects of two antiparasitic agents, similar tumor-regulation modulators chloroquine and ivermectin, in doses equivalent to human doses were observed in fibrosarcoma in hamsters (both drugs approximately 1/10 LD50) without toxicity and in various cell lines of human lung, colon and cervical carcinomas and hamster fibrosarcoma in vitro. The addition of a reciprocal modulator of cancer regulation, NF-κB stimulator deoxycholic acid, caused a huge rescue effect on fibrosarcoma and a reversal of the successful anticancer therapy using the combination. Conclusions: The chloroquine and ivermectin combination may be recommended for comprehensive additional preclinical and clinical evaluation due to its synergistic anticancer effects. Further preclinical and clinical exploration will be crucial to thoroughly define the optimal role of the combination therapy in the treatment of fibrosarcoma and potentially other cancer types.