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. 2022 Feb 4;17(2):e0262212.
doi: 10.1371/journal.pone.0262212. eCollection 2022.

A novel pro-oxidant combination of resveratrol and copper reduces transplant related toxicities in patients receiving high dose melphalan for multiple myeloma (RESCU 001)

Anshul Agarwal  1   2 , Aakanksha Khandelwal  2   3 , Kavita Pal  2   3 , Naveen Kumar Khare  2   3 , Vishal Jadhav  2   3 , Murarilal Gurjar  2   4 , Sachin Punatar  1   2 , Anant Gokarn  1   2 , Avinash Bonda  1   2 , Lingaraj Nayak  1   2 , Sadhana Kannan  2   5 , Vikram Gota  2   4 , Navin Khattry  1   2 , Indraneel Mittra  2   3
Affiliations

A novel pro-oxidant combination of resveratrol and copper reduces transplant related toxicities in patients receiving high dose melphalan for multiple myeloma (RESCU 001)

Anshul Agarwal et al. PLoS One. .

Abstract

Background: Transplant related toxicity is a major therapeutic challenge. We have previously reported that the toxicity of chemotherapy is largely not directly because of the drugs themselves; rather it is mainly due to DNA damage, apoptosis and hyper-inflammation triggered by cell-free chromatin particles that are released because of drug-induced host cell death. Cell-free chromatin particles can be inactivated by free-radicals which are generated when the nutraceuticals resveratrol and copper are administered orally. We investigated if a combination of resveratrol and copper would reduce transplant related toxicities in an exploratory, prospective dose-escalation study.

Patients and methods: Twenty-five patients with multiple myeloma were enrolled between March 2017 to August 2019. Patients were divided into 3 groups: control (Group 1, N = 5) received vehicle alone; group 2 (N = 15) received resveratrol-copper at dose level I (resveratrol = 5.6 mg and copper = 560 ng); group 3 (N = 5) received resveratrol-copper at dose level II (resveratrol = 50 mg and copper = 5 μg). The dose was given twice daily with the first dose administered 48 hours before administering melphalan and continued until day +21 post-transplant. Common Terminology Criteria for Adverse Events version 4.02 was used to assess toxicities which included oral mucositis, nausea, vomiting and diarrhea. Measurement of inflammatory cytokines was done by ELISA.

Results: All patients (100%) in the control group developed grade 3/4 oral mucositis compared to 8/20 (40%) in both resveratrol-copper group 2 plus group 3 combined (P = 0.039). Reduction in inflammatory cytokines: salivary TNF - α (p = 0.012) and IL-1β (p = 0.009) in dose level I but not in dose level II was observed.

Conclusions: A combination of resveratrol-copper reduced transplant related toxicities in patients with multiple myeloma receiving high dose melphalan. We conclude that relatively inexpensive nutraceuticals may be useful as adjuncts to chemotherapy to reduce its toxicity.

Registration: The trial was registered under Clinical Trial Registry of India (no.CTRI/2018/02/011905).

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Flow chart.
*Only clinical outcome was obtained from these patients. Cytokine levels were not measured.
See this image and copyright information in PMC

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Grants and funding

The study was supported by Tata Memorial Centre awarded to IM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.